TIM3-binding chimeric antigen receptors

ABSTRACT

Disclosed herein are chimeric antigen receptor (CAR) polypeptides that can be used with adoptive cell transfer to target and kill TIM3-expressing cancers. Also disclosed are immune effector cells, such as T cells or Natural Killer (NK) cells, that are engineered to express these CARs. Therefore, also disclosed are methods of providing an anti-tumor immunity in a subject with a TIM3-expressing cancer that involves adoptive transfer of the disclosed immune effector cells engineered to express the disclosed CARs.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims benefit of U.S. Provisional Application No.62/462,059, filed Feb. 22, 2017, and Application Ser. No. 62/592,110,filed Nov. 29, 2017, which are hereby incorporated herein by referencein their entirety.

BACKGROUND

Surgery, radiation therapy, and chemotherapy have been the standardaccepted approaches for treatment of cancers including leukemia, solidtumors, and metastases. Immunotherapy (sometimes called biologicaltherapy, biotherapy, or biological response modifier therapy), whichuses the body's immune system, either directly or indirectly, to shrinkor eradicate cancer has been studied for many years as an adjunct toconventional cancer therapy. It is believed that the human immune systemis an untapped resource for cancer therapy and that effective treatmentcan be developed once the components of the immune system are propertyharnessed.

SUMMARY

Disclosed herein are chimeric antigen receptor (CAR) polypeptides thatcan be used with adoptive cell transfer to target and killTIM3-expressing cancers. The disclosed CAR polypeptides contain in anectodomain an anti-TIM3 binding agent that can bind TIM3-expressingcancer cells. The anti-TIM3 binding agent is in some embodiments anantibody fragment that specifically binds TIM3. For example, the antigenbinding domain can be a Fab or a single-chain variable fragment (scFv)of an antibody that specifically binds TIM3. The anti-TIM3 binding agentis in some embodiments an aptamer that specifically binds TIM3. Forexample, the anti-TIM3 binding agent can be a peptide aptamer selectedfrom a random sequence pool based on its ability to bind TIM3. Theanti-TIM3 binding agent can also be a natural ligand of TIM3, or avariant and/or fragment thereof capable of binding TIM3.

In some cases, the anti-TIM3 V_(H) domain comprises the amino acidsequence QVTLKESGPGILQPSQTLSLTCSFSGFSLSTSNMAVSWIRQPSGKGLEWLALIYWDDDKRYNPSLKSRLTISKDTSRNQVFLKITSVDAADTATYYCVRSQLLRFAYWGQGTL VTVSA (SEQ IDNO:1), or a fragment or variant thereof able to bind TIM3.

In some cases, the anti-TIM3 V_(H) domain comprises the amino acidsequence QVQLQQPGAELVKPGASVKLSCKASGYTGTSYYMYWVKQRPGQGLEWIGGINPSNGGTNFNEKFKSKATLTVDKSSSTAYMQLSSLTSEDSAVYYCTTAYFDYWGQGTTL TVSS (SEQ IDNO:2), or a fragment or variant thereof able to bind TIM3.

In some cases, the anti-TIM3 V_(L) domain comprises the amino acidsequence DIQMTQSSSYLSVSLGGRVTITCKASDHINNWLAWYQQKPGNAPRLLISGATSLETGVPSRFSGRGSGKDYTLSITSLQTEDVATYYCQQYWSTPVTFGAGTKLELKAAA (SEQ ID NO:3), ora fragment or variant thereof able to bind TIM3.

In some cases, the anti-TIM3 V_(L) domain comprises the amino acidsequence DIVMTQSPATLSVTPGDRVSLSCRASQSISDYLHWYQQKSHESPRLLIKYASQSISGIPSRFSGSGSGSDFTLSINSVEPEDVGVYYCQNGHSFPRTFGGGTKLEIKAAA (SEQ ID NO:4), or afragment or variant thereof able to bind TIM3.

In some cases, the anti-TIM3 V_(L) domain comprises the amino acidsequence EIVLTQSPAITAASLGQKVTITCSASSSVSYMHWYQQKSGTSPKPWIYEISKLASGVPARFSGSGSGTSYSLTISSMEAEDAAIYYCQQWNYPLYTFGGGTKLEIKAAA (SEQ ID NO:5), or afragment or variant thereof able to bind TIM3.

In some cases, the anti-TIM3 V_(L) domain comprises the amino acidsequence QIVLTQSPAIMSASPGEKVTMSCSASPGEKVTMSCSASSSLTYMYWFQQKPGSSPKPWIYRTSNLASGVPARFSGSGSGTSYSLTISSMEAEDAATYTCQQYHSYPPTFGG GTKLEIKAAA (SEQID NO:6), or a fragment or variant thereof able to bind TIM3.

In some cases, the anti-TIM3 V_(L) domain comprises the amino acidsequence XIVXTQSPAXXSXSXGXXVTXXCXASXSXXXYXXWYQQKXGXSPXXXIXXXSXLXSGVPXRFSGSGSGXXYXLXIXSXEXEDXAXYYCQXXSXPXTFGGGTKLEIKAAA (SEQ ID NO:7),wherein “X” is any amino acid or no amino acid, or a fragment or variantthereof able to bind TIM3. Also disclosed are other consensus sequencesbased on the alignments shown in FIGS. 9 and 10, e.g. based onconservative substitutions at variable residues.

As with other CARs, the disclosed polypeptides can also contain atransmembrane domain and an endodomain capable of activating an immuneeffector cell. For example, the endodomain can contain a signalingdomain and one or more co-stimulatory signaling regions.

In some embodiments, the intracellular signaling domain is a CD3 zeta(CD3ζ) signaling domain. In some embodiments, the costimulatorysignaling region comprises the cytoplasmic domain of CD28, 4-1 BB, or acombination thereof. In some cases, the costimulatory signaling regioncontains 1, 2, 3, or 4 cytoplasmic domains of one or more intracellularsignaling and/or costimulatory molecules. In some embodiments, theco-stimulatory signaling region contains one or more mutations in thecytoplasmic domains of CD28 and/or 4-1 BB that enhance signaling.

In some embodiments, the CAR polypeptide contains an incompleteendodomain. For example, the CAR polypeptide can contain only anintracellular signaling domain or a co-stimulatory domain, but not both.In these embodiments, the immune effector cell is not activated unlessit and a second CAR polypeptide (or endogenous T-cell receptor) thatcontains the missing domain both bind their respective antigens.Therefore, in some embodiments, the CAR polypeptide contains a CD3 zeta(CD3ζ) signaling domain but does not contain a costimulatory signalingregion (CSR). In other embodiments, the CAR polypeptide contains thecytoplasmic domain of CD28, 4-1 BB, or a combination thereof, but doesnot contain a CD3 zeta (CD3ζ) signaling domain (SD).

Also disclosed are isolated nucleic acid sequences encoding thedisclosed CAR polypeptides, vectors comprising these isolated nucleicacids, and cells containing these vectors. For example, the cell can bean immune effector cell selected from the group consisting of analpha-beta T cells, a gamma-delta T cell, a Natural Killer (NK) cells, aNatural Killer T (NKT) cell, a B cell, an innate lymphoid cell (ILC), acytokine induced killer (CIK) cell, a cytotoxic T lymphocyte (CTL), alymphokine activated killer (LAK) cell, and a regulatory T cell.

In some embodiments, the cell exhibits an anti-tumor immunity when theantigen binding domain of the CAR binds to TIM3.

Also disclosed is a method of providing an anti-cancer immunity in asubject with a TIM3-expressing cancer that involves administering to thesubject an effective amount of an immune effector cell geneticallymodified with a disclosed TIM3-specific CAR. For example, in someembodiments, the cancer is a hematological cancer, such as acute myeloidleukemia (AML).

The details of one or more embodiments of the invention are set forth inthe accompanying drawings and the description below. Other features,objects, and advantages of the invention will be apparent from thedescription and drawings, and from the claims.

DESCRIPTION OF DRAWINGS

FIG. 1 is an illustration of a TIM3-specific chimeric antigen receptor(CAR).

FIG. 2 illustrates a next generation sequencing (NGS) screeningprocedure for identifying anti-TIM3 sequences. 1) immunizing mice, 2)isolate splenic B cells, 3) isolate RNA, 4) FuzeSeq™ (GENEWIZ) antibodysequencing, 5) bioinformatics analysis of IgH and IgL rearrangements toselect putative anti-TIM3 sequences, and 6) in vitro screening tovalidate.

FIG. 3 illustrates how next generation sequencing (NGS) can improve invivo discovery methods using hybridomas.

FIG. 4 illustrates the work flow of B cell antibody library profilingusing NGS. Advantages include a snapshot of antibody responses at acertain moment, in depth profiling of diverse antibody repertoire, nohumanization needed for therapeutic antibody, saves time and effortcreating and selecting hybridomas, and no dropout of high affinityantibodies due to inefficient cell fusion.

FIG. 5 illustrates the process for preparing a library for NGS.

FIG. 6 illustrates the data analysis workflow and deliverables of B cellantibody library profiling using NGS. This involves data qualitycontrol, multiplexing, and quality trimming; CDR identification andfrequency analysis; V-D-J usage an lineage frequency; and CDR lengthdistribution and CDR3 clustering.

FIGS. 7A and 7B show the most common shared VJ_(k) (FIG. 7A) andVDJ_(H)(FIG. 7B) rearrangements in three TIM3 immunized mice. Sequencesselected for validation are boxed (Vk13-85 is not in the top 10 vksequences and was included as a control).

FIG. 8 illustrates an example scFv constructed to target TIM3(IGHV812-IGKV461 scFv).

FIG. 9 is a sequence alignment of IGHV812-based anti-TIM3 scFvsequences. IGHV812 is paired with one of four IGK rearrangements tocreate 4 separate anti-TIM3 scFv. IGHV812-IGKV1385: SEQ ID NO:15;IGHV812-IGKV539: SEQ ID NO:16; IGHV812-IGKV486: SEQ ID NO:17;IGHV812-IGKV461: SEQ ID NO:18.

FIG. 10 is a sequence alignment of IGHV1S81-based anti-TIM3 scFvsequences. IGHV1S81 is paired with one of four IGK rearrangements tocreate 4 separate anti-TIM3 scFv. IGHV1S81-IGKV461: SEQ ID NO:19;IGHV1S81-IGKV539: SEQ ID NO:20; IGHV1S81-IGKV1385: SEQ ID NO:21;IGHV1S81-IGKV486: SEQ ID NO:22.

FIG. 11 shows an example anti-TIM3/BBz GFP CAR construct. Thetransmembrane and hinge domains are derived from CD8. Human 41BBintracellular co-stimulatory domain is fused to human CD3zeta.

FIGS. 12A and 12B show TIM3 retargeting of Jurkat T cells transducedwith IGHV812-based anti-TIM3 scFv. FIG. 12A shows TIM3-positive targets,and FIG. 12B shows TIM3-negative targets. Interferon-gamma is secretedonly when TIM3-positive targets are encountered.

FIGS. 13A and 13B show TIM3 retargeting of Jurkat T cells transducedwith IGHV1S81-based anti-TIM3 scFv. FIG. 13A shows TIM3-positivetargets, and FIG. 13B shows TIM3-negative targets. Interferon-gamma issecreted only when TIM3-postive targets are encountered.

FIGS. 14A to 14D show primary human T cells expressing anti-TIM3 CARscan effectively kill TIM3 target cells as measured using a Real-Timecell Analysis cytotoxicity assay. Target cells are CHO-TIM3. E:T ratioof 10:1 was used. Untransduced cells are negative control for T cells.CHO-CD20 are negative controls for targets.

FIGS. 15A to 15H show primary human T cells expressing anti-TIM3 CARscan effectively kill TIM3 target cells as measured using a Real-Timecell Analysis cytotoxicity assay. Target cells are CHO-TIM3. E:T ratioof 10:1 was used. Untransduced cells are negative control for T cells.CHO-CD20 are negative controls for targets.

FIGS. 16A to 16H show primary human T cells expressing anti-TIM3 CARscan effectively kill TIM3 target cells as measured using a Real-Timecell Analysis cytotoxicity assay. Target cells are CHO-TIM3.Untransduced cells are negative control for T cells. CHO-CD20 arenegative controls for targets. They compare killing at an E:T 10:1 vs.5:1 ratios.

FIGS. 17A and 17B show primary human T cells expressing anti-TIM3 CARscan effectively kill TIM3 target cells as measured using a Real-Timecell Analysis cytotoxicity assay. T cells were treated with TIM3blocking antibody before added to target cells. Target cells areCHO-TIM3 or CHO-CD20. E:T ratio of 10:1 was used.

FIGS. 18A to 18H show primary human T cells expressing anti-TIM3 CARscan effectively kill TIM3 target cells as measured using a Real-Timecell Analysis cytotoxicity assay. T cells were treated with TIM3blocking antibody before added to target cells. Target cells areCHO-TIM3 or CHO-CD20. E:T ratio of 10:1 was used.

FIGS. 19A to 19C show Jurkat cells expressing anti-TIM3 CAR VHS-539 haverobust gene transfer (B) and IFNγ expression (A) after stimulation withtarget cells expressing TIM3.

FIGS. 20A to 20H show primary human T cells transduced with anti-TIM3CARs have significantly increased secretion of cytokines after TIM3antigen-stimulation for 24 hr. Cytokines measured by Luminex.

FIGS. 21A and 21B show proliferation of TIM3 CAR-T in vivo and AMLKilling. FIG. 21A shows CAR T cell numbers analyzed via GFP fluorescenceshowed significant expansion of TIM3 CAR T cells in human AMLxenografted mice compared to control group. FIG. 21B shows TIM3 CAR-Twere able to kill the Human AML (CD33+CD45+) cells compared to controlCAR T untreated group in peripheral blood. NSG mice were engrafted withpatient derived AML cells via IV injection. Six weeks after confirmationof engraftment, xenografted mice were treated TIM3 directed CAR T cellsor saline as a control generated from normal healthy donor T cells.Three weeks following CAR T cells injection, mice were bled toquantitate CAR T cells proliferation and myeloid cells ablation.

DETAILED DESCRIPTION

Disclosed herein are chimeric antigen receptors (CAR) that canspecifically recognize tumor-associated antigens (TAA) onTIM3-expressing cancers. Also disclosed are immune effector cells, suchas T cells or Natural Killer (NK) cells, that are engineered to expressthese CARs. Therefore, also disclosed are methods for providing ananti-tumor immunity in a subject with TIM3-expressing cancers thatinvolves adoptive transfer of the disclosed immune effector cellsengineered to express the disclosed TIM3-specific CARs.

TIM3-Specific Chimeric Antigen Receptors (CAR)

CARs generally incorporate an antigen recognition domain from thesingle-chain variable fragments (scFv) of a monocional antibody (mAb)with transmembrane signaling motifs involved in lymphocyte activation(Sadelain M, et al. Nat Rev Cancer 2003 3:35-45). Disclosed herein is aTIM3-specific chimeric antigen receptor (CAR) that can be that can beexpressed in immune effector cells to enhance antitumor activity againstTIM3-specific CARs.

The disclosed CAR is generally made up of three domains: an ectodomain,a transmembrane domain, and an endodomain. The ectodomain comprises theTIM3-binding region and is responsible for antigen recognition. It alsooptionally contains a signal peptide (SP) so that the CAR can beglycosylated and anchored in the cell membrane of the immune effectorcell. The transmembrane domain (TD), is as its name suggests, connectsthe ectodomain to the endodomain and resides within the cell membranewhen expressed by a cell. The endodomain is the business end of the CARthat transmits an activation signal to the immune effector cell afterantigen recognition. For example, the endodomain can contain a signalingdomain (SD) and a co-stimulatory signaling region (CSR).

A “signaling domain (SD)” generally contains immunoreceptortyrosine-based activation motifs (ITAMs) that activate a signalingcascade when the ITAM is phosphorylated. The term “co-stimulatorysignaling region (CSR)” refers to intracellular signaling domains fromcostimulatory protein receptors, such as CD28, 41BB, and ICOS, that areable to enhance T-cell activation by T-cell receptors.

In some embodiments, the endodomain contains an SD or a CSR, but notboth. In these embodiments, an immune effector cell containing thedisclosed CAR is only activated if another CAR (or a T-cell receptor)containing the missing domain also binds its respective antigen.

In some embodiments, the disclosed CAR is defined by the formula:SP-TIM3-HG-TM-CSR-SD; orSP-TIM3-HG-TM-SD-CSR

wherein “SP” represents an optional signal peptide,

wherein “TIM3” represents a TIM3-binding region,

wherein “HG” represents an optional hinge domain,

wherein “TM” represents a transmembrane domain,

wherein “CSR” represents one or more co-stimulatory signaling regions,

wherein “SD” represents a signaling domain, and

wherein “—” represents a peptide bond or linker.

Additional CAR constructs are described, for example, in Fresnak A D, etal.

Engineered T cells: the promise and challenges of cancer immunotherapy.Nat Rev Cancer. 2016 Aug. 23; 16(9):566-81, which is incorporated byreference in its entirety for the teaching of these CAR models.

For example, the CAR can be a TRUCK, Universal CAR, Self-driving CAR,Armored CAR, Self-destruct CAR, Conditional CAR, Marked CAR, TenCAR,Dual CAR, or sCAR.

TRUCKs (T cells redirected for universal cytokine killing) co-express achimeric antigen receptor (CAR) and an antitumor cytokine. Cytokineexpression may be constitutive or induced by T cell activation. Targetedby CAR specificity, localized production of pro-inflammatory cytokinesrecruits endogenous immune cells to tumor sites and may potentiate anantitumor response.

Universal, allogeneic CAR T cells are engineered to no longer expressendogenous T cell receptor (TCR) and/or major histocompatibility complex(MHC) molecules, thereby preventing graft-versus-host disease (GVHD) orrejection, respectively.

Self-driving CARs co-express a CAR and a chemokine receptor, which bindsto a tumor ligand, thereby enhancing tumor homing.

CAR T cells engineered to be resistant to immunosuppression (ArmoredCARs) may be genetically modified to no longer express various immunecheckpoint molecules (for example, cytotoxic T lymphocyte-associatedantigen 4 (CTLA4) or programmed cell death protein 1 (PD1)), with animmune checkpoint switch receptor, or may be administered with amonoclonal antibody that blocks immune checkpoint signaling.

A self-destruct CAR may be designed using RNA delivered byelectroporation to encode the CAR. Alternatively, inducible apoptosis ofthe T cell may be achieved based on ganciclovir binding to thymidinekinase in gene-modified lymphocytes or the more recently describedsystem of activation of human caspase 9 by a small-molecule dimerizer.

A conditional CAR T cell is by default unresponsive, or switched ‘off’,until the addition of a small molecule to complete the circuit, enablingfull transduction of both signal 1 and signal 2, thereby activating theCAR T cell. Alternatively, T cells may be engineered to express anadaptor-specific receptor with affinity for subsequently administeredsecondary antibodies directed at target antigen.

Marked CAR T cells express a CAR plus a tumor epitope to which anexisting monocional antibody agent binds. In the setting of intolerableadverse effects, administration of the monoclonal antibody clears theCAR T cells and alleviates symptoms with no additional off-tumoreffects.

A tandem CAR (TanCAR) T cell expresses a single CAR consisting of twolinked single-chain variable fragments (scFvs) that have differentaffinities fused to intracellular co-stimulatory domain(s) and a CD3ζdomain. TanCAR T cell activation is achieved only when target cellsco-express both targets.

A dual CAR T cell expresses two separate CARs with different ligandbinding targets; one CAR includes only the CD3ζ domain and the other CARincludes only the co-stimulatory domain(s). Dual CAR T cell activationrequires co-expression of both targets on the tumor.

A safety CAR (sCAR) consists of an extracellular scFv fused to anintracellular inhibitory domain, sCAR T cells co-expressing a standardCAR become activated only when encountering target cells that possessthe standard CAR target but lack the sCAR target.

The antigen recognition domain of the disclosed CAR is usually an scFv.There are however many alternatives. An antigen recognition domain fromnative T-cell receptor (TCR) alpha and beta single chains have beendescribed, as have simple ectodomains (e.g. CD4 ectodomain to recognizeHIV infected cells) and more exotic recognition components such as alinked cytokine (which leads to recognition of cells bearing thecytokine receptor). In fact almost anything that binds a given targetwith high affinity can be used as an antigen recognition region.

The endodomain is the business end of the CAR that after antigenrecognition transmits a signal to the immune effector cell, activatingat least one of the normal effector functions of the immune effectorcell. Effector function of a T cell, for example, may be cytolyticactivity or helper activity including the secretion of cytokines.Therefore, the endodomain may comprise the “signaling domain” of a Tcell receptor (TCR). While usually the entire intracellular signalingdomain can be employed, in many cases it is not necessary to use theentire chain. To the extent that a truncated portion of theintracellular signaling domain is used, such truncated portion may beused in place of the intact chain as long as it transduces the effectorfunction signal.

Cytoplasmic signaling sequences that regulate primary activation of theTCR complex that act in a stimulatory manner may contain signalingmotifs which are known as immunoreceptor tyrosine-based activationmotifs (ITAMs). Examples of ITAM containing cytoplasmic signalingsequences include those derived from CD8, CD3ζ, CD3δ, CD3γ, CD3ε, CD32(Fc gamma RIIa), DAP10, DAP12, CD79a, CD79b, FcγRIγ, FcγRIIIγ, FcεRIβ(FCERIB), and FcεRIγ (FCERIG).

In particular embodiments, the signaling domain is derived from CD3 zeta(CD3ζ) (TCR zeta, GenBank accno. BAG36664.1). T-cell surfaceglycoprotein CD3 zeta (CD3ζ) chain, also known as T-cell receptor T3zeta chain or CD247 (Cluster of Differentiation 247), is a protein thatin humans is encoded by the CD247 gene.

First-generation CARs typically had the intracellular domain from theCD3ζ chain, which is the primary transmitter of signals from endogenousTCRs. Second-generation CARs add intracellular signaling domains fromvarious costimulatory protein receptors (e.g., CD28, 41BB, ICOS) to theendodomain of the CAR to provide additional signals to the T cell.Preclinical studies have indicated that the second generation of CARdesigns improves the antitumor activity of T cells. More recent,third-generation CARs combine multiple signaling domains to furtheraugment potency. T cells grafted with these CARs have demonstratedimproved expansion, activation, persistence, and tumor-eradicatingefficiency independent of costimulatory receptor/ligand interaction(Imai C, et al. Leukemia 2004 18:676-84; Maher J, et al. Nat Biotechnol2002 20:70-5).

For example, the endodomain of the CAR can be designed to comprise theCD3ζ signaling domain by itself or combined with any other desiredcytoplasmic domain(s) useful in the context of the CAR of the invention.For example, the cytoplasmic domain of the CAR can comprise a CD3ζ chainportion and a costimulatory signaling region. The costimulatorysignaling region refers to a portion of the CAR comprising theintracellular domain of a costimulatory molecule. A costimulatorymolecule is a cell surface molecule other than an antigen receptor ortheir ligands that is required for an efficient response of lymphocytesto an antigen. Examples of such molecules include CD27, CD28, 4-1BB(CD137), OX40, CD30, CD40, ICOS, lymphocyte function-associatedantigen-1 (LFA-1), CD2, CD7, LIGHT, NKG2C, B7-H3, and a ligand thatspecifically binds with CD83, CD8, CD4, b2c, CD80, CD86, DAP10, DAP12,MyD88, BTNL3, and NKG2D. Thus, while the CAR is exemplified primarilywith CD28 as the co-stimulatory signaling element, other costimulatoryelements can be used alone or in combination with other co-stimulatorysignaling elements.

In some embodiments, the CAR comprises a hinge sequence. A hingesequence is a short sequence of amino acids that facilitates antibodyflexibility (see, e.g., Woof et al., Nat. Rev. Immunol., 4(2): 89-99(2004)). The hinge sequence may be positioned between the antigenrecognition moiety (e.g., anti-TIM3 scFv) and the transmembrane domain.The hinge sequence can be any suitable sequence derived or obtained fromany suitable molecule. In some embodiments, for example, the hingesequence is derived from a CD8a molecule or a CD28 molecule.

The transmembrane domain may be derived either from a natural or from asynthetic source. Where the source is natural, the domain may be derivedfrom any membrane-bound or transmembrane protein. For example, thetransmembrane region may be derived from (i.e. comprise at least thetransmembrane region(s) of) the alpha, beta or zeta chain of the T-cellreceptor, CD28, CD3 epsilon, CD45, CD4, CD5, CD8 (e.g., CD8 alpha, CD8beta), CD9, CD16, CD22, CD33, CD37, CD64, CD80, CD86, CD134, CD137, orCD154, KIRDS2, OX40, CD2, CD27, LFA-1 (CD11a, CD18), ICOS (CD278), 4-1BB(CD137), GITR, CD40, BAFFR, HVEM (LIGHTR), SLAMF7, NKp80 (KLRF1), CD160,CD19, IL2R beta, IL2R gamma, IL7R α, ITGA1, VLA1, CD49a, ITGA4, IA4,CD49D, ITGA6, VLA-6, CD49f, ITGAD, CD11d, ITGAE, CD103, ITGAL, CD11a,LFA-1, ITGAM, CD11b, ITGAX, CD11c, ITGB1, CD29, ITGB2, CD18, LFA-1,ITGB7, TNFR2, DNAM1 (CD226), SLAMF4 (CD244, 2B4), CD84, CD96 (Tactile),CEACAMI, CRTAM, Ly9 (CD229), CD160 (BY55), PSGL1, CD100 (SEMA4D), SLAMF6(NTB-A, Ly108), SLAM (SLAMFI, CD150, IPO-3), BLAME (SLAMF8), SELPLG(CD162), LTBR, and PAG/Cbp. Alternatively the transmembrane domain maybe synthetic, in which case it will comprise predominantly hydrophobicresidues such as leucine and valine. In some cases, a triplet ofphenylalanine, tryptophan and valine will be found at each end of asynthetic transmembrane domain. A short oligo- or polypeptide linker,such as between 2 and 10 amino acids in length, may form the linkagebetween the transmembrane domain and the endoplasmic domain of the CAR.

In some embodiments, the CAR has more than one transmembrane domain,which can be a repeat of the same transmembrane domain, or can bedifferent transmembrane domains.

In some embodiments, the CAR is a multi-chain CAR, as described inWO2015/039523, which is incorporated by reference for this teaching. Amulti-chain CAR can comprise separate extracellular ligand binding andsignaling domains in different transmembrane polypeptides. The signalingdomains can be designed to assemble in juxtamembrane position, whichforms flexible architecture closer to natural receptors, that confersoptimal signal transduction. For example, the multi-chain CAR cancomprise a part of an FCERI alpha chain and a part of an FCERI betachain such that the FCERI chains spontaneously dimerize together to forma CAR.

Tables 1, 2, and 3 below provide some example combinations ofTIM3-binding region, co-stimulatory signaling regions, and signalingdomains that can occur in the disclosed CARs. Tables 4 to 6 provideexamples of combinations without either a signaling domain or aco-stimulatory signal region, i.e. so the CAR provides suboptimalactivation upon binding to TIM3 and requires a second CAR containing themissing domain to bind its respective antigen in order for the cell tobe activated.

TABLE 1 First Generation CARs ScFv Signal Domain TIM3 CD8 TIM3 CD3ζ TIM3CD3δ TIM3 CD3γ TIM3 CD3ε TIM3 FcγRI-γ TIM3 FcγRIII-γ TIM3 FcεRIβ TIM3FcεRIγ TIM3 DAP10 TIM3 DAP12 TIM3 CD32 TIM3 CD79a

TABLE 2 Second Generation CARs Co-stimulatory Signal Co-stimulatorySignal ScFv Signal Domain ScFv Signal Domain TIM3 CD28 CD8 TIM3 CD80FcεRIβ TIM3 CD28 CD3ζ TIM3 CD80 FcεRIγ TIM3 CD28 CD3δ TIM3 CD80 DAP10TIM3 CD28 CD3γ TIM3 CD80 DAP12 TIM3 CD28 CD3ε TIM3 CD80 CD32 TIM3 CD28FcγRI-γ TIM3 CD80 CD79a TIM3 CD28 FcγRIII-γ TIM3 CD80 CD79b TIM3 CD28FcεRIβ TIM3 CD86 CD8 TIM3 CD28 FcεRIγ TIM3 CD86 CD3ζ TIM3 CD28 DAP10TIM3 CD86 CD3δ TIM3 CD28 DAP12 TIM3 CD86 CD3γ TIM3 CD28 CD32 TIM3 CD86CD3ε TIM3 CD28 CD79a TIM3 CD86 FcγRI-γ TIM3 CD28 CD79b TIM3 CD86FcγRIII-γ TIM3 CD8 CD8 TIM3 CD86 FcεRIβ TIM3 CD8 CD3ζ TIM3 CD86 FcεRIγTIM3 CD8 CD3δ TIM3 CD86 DAP10 TIM3 CD8 CD3γ TIM3 CD86 DAP12 TIM3 CD8CD3ε TIM3 CD86 CD32 TIM3 CD8 FcγRI-γ TIM3 CD86 CD79a TIM3 CD8 FcγRIII-γTIM3 CD86 CD79b TIM3 CD8 FcεRIβ TIM3 OX40 CD8 TIM3 CD8 FcεRIγ TIM3 OX40CD3ζ TIM3 CD8 DAP10 TIM3 OX40 CD3δ TIM3 CD8 DAP12 TIM3 OX40 CD3γ TIM3CD8 CD32 TIM3 OX40 CD3ε TIM3 CD8 CD79a TIM3 OX40 FcγRI-γ TIM3 CD8 CD79bTIM3 OX40 FcγRIII-γ TIM3 CD4 CD8 TIM3 OX40 FcεRIβ TIM3 CD4 CD3ζ TIM3OX40 FcεRIγ TIM3 CD4 CD3δ TIM3 OX40 DAP10 TIM3 CD4 CD3γ TIM3 OX40 DAP12TIM3 CD4 CD3ε TIM3 OX40 CD32 TIM3 CD4 FcγRI-γ TIM3 OX40 CD79a TIM3 CD4FcγRIII-γ TIM3 OX40 CD79b TIM3 CD4 FcεRIβ TIM3 DAP10 CD8 TIM3 CD4 FcεRIγTIM3 DAP10 CD3ζ TIM3 CD4 DAP10 TIM3 DAP10 CD3δ TIM3 CD4 DAP12 TIM3 DAP10CD3γ TIM3 CD4 CD32 TIM3 DAP10 CD3ε TIM3 CD4 CD79a TIM3 DAP10 FcγRI-γTIM3 CD4 CD79b TIM3 DAP10 FcγRIII-γ TIM3 b2c CD8 TIM3 DAP10 FcεRIβ TIM3b2c CD3ζ TIM3 DAP10 FcεRIγ TIM3 b2c CD3δ TIM3 DAP10 DAP10 TIM3 b2c CD3γTIM3 DAP10 DAP12 TIM3 b2c CD3ε TIM3 DAP10 CD32 TIM3 b2c FcγRI-γ TIM3DAP10 CD79a TIM3 b2c FcγRIII-γ TIM3 DAP10 CD79b TIM3 b2c FcεRIβ TIM3DAP12 CD8 TIM3 b2c FcεRIγ TIM3 DAP12 CD3ζ TIM3 b2c DAP10 TIM3 DAP12 CD3δTIM3 b2c DAP12 TIM3 DAP12 CD3γ TIM3 b2c CD32 TIM3 DAP12 CD3ε TIM3 b2cCD79a TIM3 DAP12 FcγRI-γ TIM3 b2c CD79b TIM3 DAP12 FcγRIII-γ TIM3CD137/41BB CD8 TIM3 DAP12 FcεRIβ TIM3 CD137/41BB CD3ζ TIM3 DAP12 FcεRIγTIM3 CD137/41BB CD3δ TIM3 DAP12 DAP10 TIM3 CD137/41BB CD3γ TIM3 DAP12DAP12 TIM3 CD137/41BB CD3ε TIM3 DAP12 CD32 TIM3 CD137/41BB FcγRI-γ TIM3DAP12 CD79a TIM3 CD137/41BB FcγRIII-γ TIM3 DAP12 CD79b TIM3 CD137/41BBFcεRIβ TIM3 MyD88 CD8 TIM3 CD137/41BB FcεRIγ TIM3 MyD88 CD3ζ TIM3CD137/41BB DAP10 TIM3 MyD88 CD3δ TIM3 CD137/41BB DAP12 TIM3 MyD88 CD3γTIM3 CD137/41BB CD32 TIM3 MyD88 CD3ε TIM3 CD137/41BB CD79a TIM3 MyD88FcγRI-γ TIM3 CD137/41BB CD79b TIM3 MyD88 FcγRIII-γ TIM3 ICOS CD8 TIM3MyD88 FcεRIβ TIM3 ICOS CD3ζ TIM3 MyD88 FcεRIγ TIM3 ICOS CD3δ TIM3 MyD88DAP10 TIM3 ICOS CD3γ TIM3 MyD88 DAP12 TIM3 ICOS CD3ε TIM3 MyD88 CD32TIM3 ICOS FcγRI-γ TIM3 MyD88 CD79a TIM3 ICOS FcγRIII-γ TIM3 MyD88 CD79bTIM3 ICOS FcεRIβ TIM3 CD7 CD8 TIM3 ICOS FcεRIγ TIM3 CD7 CD3ζ TIM3 ICOSDAP10 TIM3 CD7 CD3δ TIM3 ICOS DAP12 TIM3 CD7 CD3γ TIM3 ICOS CD32 TIM3CD7 CD3ε TIM3 ICOS CD79a TIM3 CD7 FcγRI-γ TIM3 ICOS CD79b TIM3 CD7FcγRIII-γ TIM3 CD27 CD8 TIM3 CD7 FcεRIβ TIM3 CD27 CD3ζ TIM3 CD7 FcεRIγTIM3 CD27 CD3δ TIM3 CD7 DAP10 TIM3 CD27 CD3γ TIM3 CD7 DAP12 TIM3 CD27CD3ε TIM3 CD7 CD32 TIM3 CD27 FcγRI-γ TIM3 CD7 CD79a TIM3 CD27 FcγRIII-γTIM3 CD7 CD79b TIM3 CD27 FcεRIβ TIM3 BTNL3 CD8 TIM3 CD27 FcεRIγ TIM3BTNL3 CD3ζ TIM3 CD27 DAP10 TIM3 BTNL3 CD3δ TIM3 CD27 DAP12 TIM3 BTNL3CD3γ TIM3 CD27 CD32 TIM3 BTNL3 CD3ε TIM3 CD27 CD79a TIM3 BTNL3 FcγRI-γTIM3 CD27 CD79b TIM3 BTNL3 FcγRIII-γ TIM3 CD28δ CD8 TIM3 BTNL3 FcεRIβTIM3 CD28δ CD3ζ TIM3 BTNL3 FcεRIγ TIM3 CD28δ CD3δ TIM3 BTNL3 DAP10 TIM3CD28δ CD3γ TIM3 BTNL3 DAP12 TIM3 CD28δ CD3ε TIM3 BTNL3 CD32 TIM3 CD28δFcγRI-γ TIM3 BTNL3 CD79a TIM3 CD28δ FcγRIII-γ TIM3 BTNL3 CD79b TIM3CD28δ FcεRIβ TIM3 NKG2D CD8 TIM3 CD28δ FcεRIγ TIM3 NKG2D CD3ζ TIM3 CD28δDAP10 TIM3 NKG2D CD3δ TIM3 CD28δ DAP12 TIM3 NKG2D CD3γ TIM3 CD28δ CD32TIM3 NKG2D CD3ε TIM3 CD28δ CD79a TIM3 NKG2D FcγRI-γ TIM3 CD28δ CD79bTIM3 NKG2D FcγRIII-γ TIM3 CD80 CD8 TIM3 NKG2D FcεRIβ TIM3 CD80 CD3ζ TIM3NKG2D FcεRIγ TIM3 CD80 CD3δ TIM3 NKG2D DAP10 TIM3 CD80 CD3γ TIM3 NKG2DDAP12 TIM3 CD80 CD3ε TIM3 NKG2D CD32 TIM3 CD80 FcγRI-γ TIM3 NKG2D CD79aTIM3 CD80 FcγRIII-γ TIM3 NKG2D CD79b

TABLE 3 Third Generation CARs Co-stimulatory Co-stimulatory Signal ScFvSignal Signal Domain TIM3 CD28 CD28 CD8 TIM3 CD28 CD28 CD3ζ TIM3 CD28CD28 CD3δ TIM3 CD28 CD28 CD3γ TIM3 CD28 CD28 CD3ε TIM3 CD28 CD28 FcγRI-γTIM3 CD28 CD28 FcγRIII-γ TIM3 CD28 CD28 FcεRIβ TIM3 CD28 CD28 FcεRIγTIM3 CD28 CD28 DAP10 TIM3 CD28 CD28 DAP12 TIM3 CD28 CD28 CD32 TIM3 CD28CD28 CD79a TIM3 CD28 CD28 CD79b TIM3 CD28 CD8 CD8 TIM3 CD28 CD8 CD3ζTIM3 CD28 CD8 CD3δ TIM3 CD28 CD8 CD3γ TIM3 CD28 CD8 CD3ε TIM3 CD28 CD8FcγRI-γ TIM3 CD28 CD8 FcγRIII-γ TIM3 CD28 CD8 FcεRIβ TIM3 CD28 CD8FcεRIγ TIM3 CD28 CD8 DAP10 TIM3 CD28 CD8 DAP12 TIM3 CD28 CD8 CD32 TIM3CD28 CD8 CD79a TIM3 CD28 CD8 CD79b TIM3 CD28 CD4 CD8 TIM3 CD28 CD4 CD3ζTIM3 CD28 CD4 CD3δ TIM3 CD28 CD4 CD3γ TIM3 CD28 CD4 CD3ε TIM3 CD28 CD4FcγRI-γ TIM3 CD28 CD4 FcγRIII-γ TIM3 CD28 CD4 FcεRIβ TIM3 CD28 CD4FcεRIγ TIM3 CD28 CD4 DAP10 TIM3 CD28 CD4 DAP12 TIM3 CD28 CD4 CD32 TIM3CD28 CD4 CD79a TIM3 CD28 CD4 CD79b TIM3 CD28 b2c CD8 TIM3 CD28 b2c CD3ζTIM3 CD28 b2c CD3δ TIM3 CD28 b2c CD3γ TIM3 CD28 b2c CD3ε TIM3 CD28 b2cFcγRI-γ TIM3 CD28 b2c FcγRIII-γ TIM3 CD28 b2c FcεRIβ TIM3 CD28 b2cFcεRIγ TIM3 CD28 b2c DAP10 TIM3 CD28 b2c DAP12 TIM3 CD28 b2c CD32 TIM3CD28 b2c CD79a TIM3 CD28 b2c CD79b TIM3 CD28 CD137/41BB CD8 TIM3 CD28CD137/41BB CD3ζ TIM3 CD28 CD137/41BB CD3δ TIM3 CD28 CD137/41BB CD3γ TIM3CD28 CD137/41BB CD3ε TIM3 CD28 CD137/41BB FcγRI-γ TIM3 CD28 CD137/41BBFcγRIII-γ TIM3 CD28 CD137/41BB FcεRIβ TIM3 CD28 CD137/41BB FcεRIγ TIM3CD28 CD137/41BB DAP10 TIM3 CD28 CD137/41BB DAP12 TIM3 CD28 CD137/41BBCD32 TIM3 CD28 CD137/41BB CD79a TIM3 CD28 CD137/41BB CD79b TIM3 CD28ICOS CD8 TIM3 CD28 ICOS CD3ζ TIM3 CD28 ICOS CD3δ TIM3 CD28 ICOS CD3γTIM3 CD28 ICOS CD3ε TIM3 CD28 ICOS FcγRI-γ TIM3 CD28 ICOS FcγRIII-γ TIM3CD28 ICOS FcεRIβ TIM3 CD28 ICOS FcεRIγ TIM3 CD28 ICOS DAP10 TIM3 CD28ICOS DAP12 TIM3 CD28 ICOS CD32 TIM3 CD28 ICOS CD79a TIM3 CD28 ICOS CD79bTIM3 CD28 CD27 CD8 TIM3 CD28 CD27 CD3ζ TIM3 CD28 CD27 CD3δ TIM3 CD28CD27 CD3γ TIM3 CD28 CD27 CD3ε TIM3 CD28 CD27 FcγRI-γ TIM3 CD28 CD27FcγRIII-γ TIM3 CD28 CD27 FcεRIβ TIM3 CD28 CD27 FcεRIγ TIM3 CD28 CD27DAP10 TIM3 CD28 CD27 DAP12 TIM3 CD28 CD27 CD32 TIM3 CD28 CD27 CD79a TIM3CD28 CD27 CD79b TIM3 CD28 CD28δ CD8 TIM3 CD28 CD28δ CD3ζ TIM3 CD28 CD28δCD3δ TIM3 CD28 CD28δ CD3γ TIM3 CD28 CD28δ CD3ε TIM3 CD28 CD28δ FcγRI-γTIM3 CD28 CD28δ FcγRIII-γ TIM3 CD28 CD28δ FcεRIβ TIM3 CD28 CD28δ FcεRIγTIM3 CD28 CD28δ DAP10 TIM3 CD28 CD28δ DAP12 TIM3 CD28 CD28δ CD32 TIM3CD28 CD28δ CD79a TIM3 CD28 CD28δ CD79b TIM3 CD28 CD80 CD8 TIM3 CD28 CD80CD3ζ TIM3 CD28 CD80 CD3δ TIM3 CD28 CD80 CD3γ TIM3 CD28 CD80 CD3ε TIM3CD28 CD80 FcγRI-γ TIM3 CD28 CD80 FcγRIII-γ TIM3 CD28 CD80 FcεRIβ TIM3CD28 CD80 FcεRIγ TIM3 CD28 CD80 DAP10 TIM3 CD28 CD80 DAP12 TIM3 CD28CD80 CD32 TIM3 CD28 CD80 CD79a TIM3 CD28 CD80 CD79b TIM3 CD28 CD86 CD8TIM3 CD28 CD86 CD3ζ TIM3 CD28 CD86 CD3δ TIM3 CD28 CD86 CD3γ TIM3 CD28CD86 CD3ε TIM3 CD28 CD86 FcγRI-γ TIM3 CD28 CD86 FcγRIII-γ TIM3 CD28 CD86FcεRIβ TIM3 CD28 CD86 FcεRIγ TIM3 CD28 CD86 DAP10 TIM3 CD28 CD86 DAP12TIM3 CD28 CD86 CD32 TIM3 CD28 CD86 CD79a TIM3 CD28 CD86 CD79b TIM3 CD28OX40 CD8 TIM3 CD28 OX40 CD3ζ TIM3 CD28 OX40 CD3δ TIM3 CD28 OX40 CD3γTIM3 CD28 OX40 CD3ε TIM3 CD28 OX40 FcγRI-γ TIM3 CD28 OX40 FcγRIII-γ TIM3CD28 OX40 FcεRIβ TIM3 CD28 OX40 FcεRIγ TIM3 CD28 OX40 DAP10 TIM3 CD28OX40 DAP12 TIM3 CD28 OX40 CD32 TIM3 CD28 OX40 CD79a TIM3 CD28 OX40 CD79bTIM3 CD28 DAP10 CD8 TIM3 CD28 DAP10 CD3ζ TIM3 CD28 DAP10 CD3δ TIM3 CD28DAP10 CD3γ TIM3 CD28 DAP10 CD3ε TIM3 CD28 DAP10 FcγRI-γ TIM3 CD28 DAP10FcγRIII-γ TIM3 CD28 DAP10 FcεRIβ TIM3 CD28 DAP10 FcεRIγ TIM3 CD28 DAP10DAP10 TIM3 CD28 DAP10 DAP12 TIM3 CD28 DAP10 CD32 TIM3 CD28 DAP10 CD79aTIM3 CD28 DAP10 CD79b TIM3 CD28 DAP12 CD8 TIM3 CD28 DAP12 CD3ζ TIM3 CD28DAP12 CD3δ TIM3 CD28 DAP12 CD3γ TIM3 CD28 DAP12 CD3ε TIM3 CD28 DAP12FcγRI-γ TIM3 CD28 DAP12 FcγRIII-γ TIM3 CD28 DAP12 FcεRIβ TIM3 CD28 DAP12FcεRIγ TIM3 CD28 DAP12 DAP10 TIM3 CD28 DAP12 DAP12 TIM3 CD28 DAP12 CD32TIM3 CD28 DAP12 CD79a TIM3 CD28 DAP12 CD79b TIM3 CD28 MyD88 CD8 TIM3CD28 MyD88 CD3ζ TIM3 CD28 MyD88 CD3δ TIM3 CD28 MyD88 CD3γ TIM3 CD28MyD88 CD3ε TIM3 CD28 MyD88 FcγRI-γ TIM3 CD28 MyD88 FcγRIII-γ TIM3 CD28MyD88 FcεRIβ TIM3 CD28 MyD88 FcεRIγ TIM3 CD28 MyD88 DAP10 TIM3 CD28MyD88 DAP12 TIM3 CD28 MyD88 CD32 TIM3 CD28 MyD88 CD79a TIM3 CD28 MyD88CD79b TIM3 CD28 CD7 CD8 TIM3 CD28 CD7 CD3ζ TIM3 CD28 CD7 CD3δ TIM3 CD28CD7 CD3γ TIM3 CD28 CD7 CD3ε TIM3 CD28 CD7 FcγRI-γ TIM3 CD28 CD7FcγRIII-γ TIM3 CD28 CD7 FcεRIβ TIM3 CD28 CD7 FcεRIγ TIM3 CD28 CD7 DAP10TIM3 CD28 CD7 DAP12 TIM3 CD28 CD7 CD32 TIM3 CD28 CD7 CD79a TIM3 CD28 CD7CD79b TIM3 CD28 BTNL3 CD8 TIM3 CD28 BTNL3 CD3ζ TIM3 CD28 BTNL3 CD3δ TIM3CD28 BTNL3 CD3γ TIM3 CD28 BTNL3 CD3ε TIM3 CD28 BTNL3 FcγRI-γ TIM3 CD28BTNL3 FcγRIII-γ TIM3 CD28 BTNL3 FcεRIβ TIM3 CD28 BTNL3 FcεRIγ TIM3 CD28BTNL3 DAP10 TIM3 CD28 BTNL3 DAP12 TIM3 CD28 BTNL3 CD32 TIM3 CD28 BTNL3CD79a TIM3 CD28 BTNL3 CD79b TIM3 CD28 NKG2D CD8 TIM3 CD28 NKG2D CD3ζTIM3 CD28 NKG2D CD3δ TIM3 CD28 NKG2D CD3γ TIM3 CD28 NKG2D CD3ε TIM3 CD28NKG2D FcγRI-γ TIM3 CD28 NKG2D FcγRIII-γ TIM3 CD28 NKG2D FcεRIβ TIM3 CD28NKG2D FcεRIγ TIM3 CD28 NKG2D DAP10 TIM3 CD28 NKG2D DAP12 TIM3 CD28 NKG2DCD32 TIM3 CD28 NKG2D CD79a TIM3 CD28 NKG2D CD79b TIM3 CD8 CD28 CD8 TIM3CD8 CD28 CD3ζ TIM3 CD8 CD28 CD3δ TIM3 CD8 CD28 CD3γ TIM3 CD8 CD28 CD3εTIM3 CD8 CD28 FcγRI-γ TIM3 CD8 CD28 FcγRIII-γ TIM3 CD8 CD28 FcεRIβ TIM3CD8 CD28 FcεRIγ TIM3 CD8 CD28 DAP10 TIM3 CD8 CD28 DAP12 TIM3 CD8 CD28CD32 TIM3 CD8 CD28 CD79a TIM3 CD8 CD28 CD79b TIM3 CD8 CD8 CD8 TIM3 CD8CD8 CD3ζ TIM3 CD8 CD8 CD3δ TIM3 CD8 CD8 CD3γ TIM3 CD8 CD8 CD3ε TIM3 CD8CD8 FcγRI-γ TIM3 CD8 CD8 FcγRIII-γ TIM3 CD8 CD8 FcεRIβ TIM3 CD8 CD8FcεRIγ TIM3 CD8 CD8 DAP10 TIM3 CD8 CD8 DAP12 TIM3 CD8 CD8 CD32 TIM3 CD8CD8 CD79a TIM3 CD8 CD8 CD79b TIM3 CD8 CD4 CD8 TIM3 CD8 CD4 CD3ζ TIM3 CD8CD4 CD3δ TIM3 CD8 CD4 CD3γ TIM3 CD8 CD4 CD3ε TIM3 CD8 CD4 FcγRI-γ TIM3CD8 CD4 FcγRIII-γ TIM3 CD8 CD4 FcεRIβ TIM3 CD8 CD4 FcεRIγ TIM3 CD8 CD4DAP10 TIM3 CD8 CD4 DAP12 TIM3 CD8 CD4 CD32 TIM3 CD8 CD4 CD79a TIM3 CD8CD4 CD79b TIM3 CD8 b2c CD8 TIM3 CD8 b2c CD3ζ TIM3 CD8 b2c CD3δ TIM3 CD8b2c CD3γ TIM3 CD8 b2c CD3ε TIM3 CD8 b2c FcγRI-γ TIM3 CD8 b2c FcγRIII-γTIM3 CD8 b2c FcεRIβ TIM3 CD8 b2c FcεRIγ TIM3 CD8 b2c DAP10 TIM3 CD8 b2cDAP12 TIM3 CD8 b2c CD32 TIM3 CD8 b2c CD79a TIM3 CD8 b2c CD79b TIM3 CD8CD137/41BB CD8 TIM3 CD8 CD137/41BB CD3ζ TIM3 CD8 CD137/41BB CD3δ TIM3CD8 CD137/41BB CD3γ TIM3 CD8 CD137/41BB CD3ε TIM3 CD8 CD137/41BB FcγRI-γTIM3 CD8 CD137/41BB FcγRIII-γ TIM3 CD8 CD137/41BB FcεRIβ TIM3 CD8CD137/41BB FcεRIγ TIM3 CD8 CD137/41BB DAP10 TIM3 CD8 CD137/41BB DAP12TIM3 CD8 CD137/41BB CD32 TIM3 CD8 CD137/41BB CD79a TIM3 CD8 CD137/41BBCD79b TIM3 CD8 ICOS CD8 TIM3 CD8 ICOS CD3ζ TIM3 CD8 ICOS CD3δ TIM3 CD8ICOS CD3γ TIM3 CD8 ICOS CD3ε TIM3 CD8 ICOS FcγRI-γ TIM3 CD8 ICOSFcγRIII-γ TIM3 CD8 ICOS FcεRIβ TIM3 CD8 ICOS FcεRIγ TIM3 CD8 ICOS DAP10TIM3 CD8 ICOS DAP12 TIM3 CD8 ICOS CD32 TIM3 CD8 ICOS CD79a TIM3 CD8 ICOSCD79b TIM3 CD8 CD27 CD8 TIM3 CD8 CD27 CD3ζ TIM3 CD8 CD27 CD3δ TIM3 CD8CD27 CD3γ TIM3 CD8 CD27 CD3ε TIM3 CD8 CD27 FcγRI-γ TIM3 CD8 CD27FcγRIII-γ TIM3 CD8 CD27 FcεRIβ TIM3 CD8 CD27 FcεRIγ TIM3 CD8 CD27 DAP10TIM3 CD8 CD27 DAP12 TIM3 CD8 CD27 CD32 TIM3 CD8 CD27 CD79a TIM3 CD8 CD27CD79b TIM3 CD8 CD28δ CD8 TIM3 CD8 CD28δ CD3ζ TIM3 CD8 CD28δ CD3δ TIM3CD8 CD28δ CD3γ TIM3 CD8 CD28δ CD3ε TIM3 CD8 CD28δ FcγRI-γ TIM3 CD8 CD28δFcγRIII-γ TIM3 CD8 CD28δ FcεRIβ TIM3 CD8 CD28δ FcεRIγ TIM3 CD8 CD28δDAP10 TIM3 CD8 CD28δ DAP12 TIM3 CD8 CD28δ CD32 TIM3 CD8 CD28δ CD79a TIM3CD8 CD28δ CD79b TIM3 CD8 CD80 CD8 TIM3 CD8 CD80 CD3ζ TIM3 CD8 CD80 CD3δTIM3 CD8 CD80 CD3γ TIM3 CD8 CD80 CD3ε TIM3 CD8 CD80 FcγRI-γ TIM3 CD8CD80 FcγRIII-γ TIM3 CD8 CD80 FcεRIβ TIM3 CD8 CD80 FcεRIγ TIM3 CD8 CD80DAP10 TIM3 CD8 CD80 DAP12 TIM3 CD8 CD80 CD32 TIM3 CD8 CD80 CD79a TIM3CD8 CD80 CD79b TIM3 CD8 CD86 CD8 TIM3 CD8 CD86 CD3ζ TIM3 CD8 CD86 CD3δTIM3 CD8 CD86 CD3γ TIM3 CD8 CD86 CD3ε TIM3 CD8 CD86 FcγRI-γ TIM3 CD8CD86 FcγRIII-γ TIM3 CD8 CD86 FcεRIβ TIM3 CD8 CD86 FcεRIγ TIM3 CD8 CD86DAP10 TIM3 CD8 CD86 DAP12 TIM3 CD8 CD86 CD32 TIM3 CD8 CD86 CD79a TIM3CD8 CD86 CD79b TIM3 CD8 OX40 CD8 TIM3 CD8 OX40 CD3ζ TIM3 CD8 OX40 CD3δTIM3 CD8 OX40 CD3γ TIM3 CD8 OX40 CD3ε TIM3 CD8 OX40 FcγRI-γ TIM3 CD8OX40 FcγRIII-γ TIM3 CD8 OX40 FcεRIβ TIM3 CD8 OX40 FcεRIγ TIM3 CD8 OX40DAP10 TIM3 CD8 OX40 DAP12 TIM3 CD8 OX40 CD32 TIM3 CD8 OX40 CD79a TIM3CD8 OX40 CD79b TIM3 CD8 DAP10 CD8 TIM3 CD8 DAP10 CD3ζ TIM3 CD8 DAP10CD3δ TIM3 CD8 DAP10 CD3γ TIM3 CD8 DAP10 CD3ε TIM3 CD8 DAP10 FcγRI-γ TIM3CD8 DAP10 FcγRIII-γ TIM3 CD8 DAP10 FcεRIβ TIM3 CD8 DAP10 FcεRIγ TIM3 CD8DAP10 DAP10 TIM3 CD8 DAP10 DAP12 TIM3 CD8 DAP10 CD32 TIM3 CD8 DAP10CD79a TIM3 CD8 DAP10 CD79b TIM3 CD8 DAP12 CD8 TIM3 CD8 DAP12 CD3ζ TIM3CD8 DAP12 CD3δ TIM3 CD8 DAP12 CD3γ TIM3 CD8 DAP12 CD3ε TIM3 CD8 DAP12FcγRI-γ TIM3 CD8 DAP12 FcγRIII-γ TIM3 CD8 DAP12 FcεRIβ TIM3 CD8 DAP12FcεRIγ TIM3 CD8 DAP12 DAP10 TIM3 CD8 DAP12 DAP12 TIM3 CD8 DAP12 CD32TIM3 CD8 DAP12 CD79a TIM3 CD8 DAP12 CD79b TIM3 CD8 MyD88 CD8 TIM3 CD8MyD88 CD3ζ TIM3 CD8 MyD88 CD3δ TIM3 CD8 MyD88 CD3γ TIM3 CD8 MyD88 CD3εTIM3 CD8 MyD88 FcγRI-γ TIM3 CD8 MyD88 FcγRIII-γ TIM3 CD8 MyD88 FcεRIβTIM3 CD8 MyD88 FcεRIγ TIM3 CD8 MyD88 DAP10 TIM3 CD8 MyD88 DAP12 TIM3 CD8MyD88 CD32 TIM3 CD8 MyD88 CD79a TIM3 CD8 MyD88 CD79b TIM3 CD8 CD7 CD8TIM3 CD8 CD7 CD3ζ TIM3 CD8 CD7 CD3δ TIM3 CD8 CD7 CD3γ TIM3 CD8 CD7 CD3εTIM3 CD8 CD7 FcγRI-γ TIM3 CD8 CD7 FcγRIII-γ TIM3 CD8 CD7 FcεRIβ TIM3 CD8CD7 FcεRIγ TIM3 CD8 CD7 DAP10 TIM3 CD8 CD7 DAP12 TIM3 CD8 CD7 CD32 TIM3CD8 CD7 CD79a TIM3 CD8 CD7 CD79b TIM3 CD8 BTNL3 CD8 TIM3 CD8 BTNL3 CD3ζTIM3 CD8 BTNL3 CD3δ TIM3 CD8 BTNL3 CD3γ TIM3 CD8 BTNL3 CD3ε TIM3 CD8BTNL3 FcγRI-γ TIM3 CD8 BTNL3 FcγRIII-γ TIM3 CD8 BTNL3 FcεRIβ TIM3 CD8BTNL3 FcεRIγ TIM3 CD8 BTNL3 DAP10 TIM3 CD8 BTNL3 DAP12 TIM3 CD8 BTNL3CD32 TIM3 CD8 BTNL3 CD79a TIM3 CD8 BTNL3 CD79b TIM3 CD8 NKG2D CD8 TIM3CD8 NKG2D CD3ζ TIM3 CD8 NKG2D CD3δ TIM3 CD8 NKG2D CD3γ TIM3 CD8 NKG2DCD3ε TIM3 CD8 NKG2D FcγRI-γ TIM3 CD8 NKG2D FcγRIII-γ TIM3 CD8 NKG2DFcεRIβ TIM3 CD8 NKG2D FcεRIγ TIM3 CD8 NKG2D DAP10 TIM3 CD8 NKG2D DAP12TIM3 CD8 NKG2D CD32 TIM3 CD8 NKG2D CD79a TIM3 CD8 NKG2D CD79b TIM3 CD4CD28 CD8 TIM3 CD4 CD28 CD3ζ TIM3 CD4 CD28 CD3δ TIM3 CD4 CD28 CD3γ TIM3CD4 CD28 CD3ε TIM3 CD4 CD28 FcγRI-γ TIM3 CD4 CD28 FcγRIII-γ TIM3 CD4CD28 FcεRIβ TIM3 CD4 CD28 FcεRIγ TIM3 CD4 CD28 DAP10 TIM3 CD4 CD28 DAP12TIM3 CD4 CD28 CD32 TIM3 CD4 CD28 CD79a TIM3 CD4 CD28 CD79b TIM3 CD4 CD8CD8 TIM3 CD4 CD8 CD3ζ TIM3 CD4 CD8 CD3δ TIM3 CD4 CD8 CD3γ TIM3 CD4 CD8CD3ε TIM3 CD4 CD8 FcγRI-γ TIM3 CD4 CD8 FcγRIII-γ TIM3 CD4 CD8 FcεRIβTIM3 CD4 CD8 FcεRIγ TIM3 CD4 CD8 DAP10 TIM3 CD4 CD8 DAP12 TIM3 CD4 CD8CD32 TIM3 CD4 CD8 CD79a TIM3 CD4 CD8 CD79b TIM3 CD4 CD4 CD8 TIM3 CD4 CD4CD3ζ TIM3 CD4 CD4 CD3δ TIM3 CD4 CD4 CD3γ TIM3 CD4 CD4 CD3ε TIM3 CD4 CD4FcγRI-γ TIM3 CD4 CD4 FcγRIII-γ TIM3 CD4 CD4 FcεRIβ TIM3 CD4 CD4 FcεRIγTIM3 CD4 CD4 DAP10 TIM3 CD4 CD4 DAP12 TIM3 CD4 CD4 CD32 TIM3 CD4 CD4CD79a TIM3 CD4 CD4 CD79b TIM3 CD4 b2c CD8 TIM3 CD4 b2c CD3ζ TIM3 CD4 b2cCD3δ TIM3 CD4 b2c CD3γ TIM3 CD4 b2c CD3ε TIM3 CD4 b2c FcγRI-γ TIM3 CD4b2c FcγRIII-γ TIM3 CD4 b2c FcεRIβ TIM3 CD4 b2c FcεRIγ TIM3 CD4 b2c DAP10TIM3 CD4 b2c DAP12 TIM3 CD4 b2c CD32 TIM3 CD4 b2c CD79a TIM3 CD4 b2cCD79b TIM3 CD4 CD137/41BB CD8 TIM3 CD4 CD137/41BB CD3ζ TIM3 CD4CD137/41BB CD3δ TIM3 CD4 CD137/41BB CD3γ TIM3 CD4 CD137/41BB CD3ε TIM3CD4 CD137/41BB FcγRI-γ TIM3 CD4 CD137/41BB FcγRIII-γ TIM3 CD4 CD137/41BBFcεRIβ TIM3 CD4 CD137/41BB FcεRIγ TIM3 CD4 CD137/41BB DAP10 TIM3 CD4CD137/41BB DAP12 TIM3 CD4 CD137/41BB CD32 TIM3 CD4 CD137/41BB CD79a TIM3CD4 CD137/41BB CD79b TIM3 CD4 ICOS CD8 TIM3 CD4 ICOS CD3ζ TIM3 CD4 ICOSCD3δ TIM3 CD4 ICOS CD3γ TIM3 CD4 ICOS CD3ε TIM3 CD4 ICOS FcγRI-γ TIM3CD4 ICOS FcγRIII-γ TIM3 CD4 ICOS FcεRIβ TIM3 CD4 ICOS FcεRIγ TIM3 CD4ICOS DAP10 TIM3 CD4 ICOS DAP12 TIM3 CD4 ICOS CD32 TIM3 CD4 ICOS CD79aTIM3 CD4 ICOS CD79b TIM3 CD4 CD27 CD8 TIM3 CD4 CD27 CD3ζ TIM3 CD4 CD27CD3δ TIM3 CD4 CD27 CD3γ TIM3 CD4 CD27 CD3ε TIM3 CD4 CD27 FcγRI-γ TIM3CD4 CD27 FcγRIII-γ TIM3 CD4 CD27 FcεRIβ TIM3 CD4 CD27 FcεRIγ TIM3 CD4CD27 DAP10 TIM3 CD4 CD27 DAP12 TIM3 CD4 CD27 CD32 TIM3 CD4 CD27 CD79aTIM3 CD4 CD27 CD79b TIM3 CD4 CD28δ CD8 TIM3 CD4 CD28δ CD3ζ TIM3 CD4CD28δ CD3δ TIM3 CD4 CD28δ CD3γ TIM3 CD4 CD28δ CD3ε TIM3 CD4 CD28δFcγRI-γ TIM3 CD4 CD28δ FcγRIII-γ TIM3 CD4 CD28δ FcεRIβ TIM3 CD4 CD28δFcεRIγ TIM3 CD4 CD28δ DAP10 TIM3 CD4 CD28δ DAP12 TIM3 CD4 CD28δ CD32TIM3 CD4 CD28δ CD79a TIM3 CD4 CD28δ CD79b TIM3 CD4 CD80 CD8 TIM3 CD4CD80 CD3ζ TIM3 CD4 CD80 CD3δ TIM3 CD4 CD80 CD3γ TIM3 CD4 CD80 CD3ε TIM3CD4 CD80 FcγRI-γ TIM3 CD4 CD80 FcγRIII-γ TIM3 CD4 CD80 FcεRIβ TIM3 CD4CD80 FcεRIγ TIM3 CD4 CD80 DAP10 TIM3 CD4 CD80 DAP12 TIM3 CD4 CD80 CD32TIM3 CD4 CD80 CD79a TIM3 CD4 CD80 CD79b TIM3 CD4 CD86 CD8 TIM3 CD4 CD86CD3ζ TIM3 CD4 CD86 CD3δ TIM3 CD4 CD86 CD3γ TIM3 CD4 CD86 CD3ε TIM3 CD4CD86 FcγRI-γ TIM3 CD4 CD86 FcγRIII-γ TIM3 CD4 CD86 FcεRIβ TIM3 CD4 CD86FcεRIγ TIM3 CD4 CD86 DAP10 TIM3 CD4 CD86 DAP12 TIM3 CD4 CD86 CD32 TIM3CD4 CD86 CD79a TIM3 CD4 CD86 CD79b TIM3 CD4 OX40 CD8 TIM3 CD4 OX40 CD3ζTIM3 CD4 OX40 CD3δ TIM3 CD4 OX40 CD3γ TIM3 CD4 OX40 CD3ε TIM3 CD4 OX40FcγRI-γ TIM3 CD4 OX40 FcγRIII-γ TIM3 CD4 OX40 FcεRIβ TIM3 CD4 OX40FcεRIγ TIM3 CD4 OX40 DAP10 TIM3 CD4 OX40 DAP12 TIM3 CD4 OX40 CD32 TIM3CD4 OX40 CD79a TIM3 CD4 OX40 CD79b TIM3 CD4 DAP10 CD8 TIM3 CD4 DAP10CD3ζ TIM3 CD4 DAP10 CD3δ TIM3 CD4 DAP10 CD3γ TIM3 CD4 DAP10 CD3ε TIM3CD4 DAP10 FcγRI-γ TIM3 CD4 DAP10 FcγRIII-γ TIM3 CD4 DAP10 FcεRIβ TIM3CD4 DAP10 FcεRIγ TIM3 CD4 DAP10 DAP10 TIM3 CD4 DAP10 DAP12 TIM3 CD4DAP10 CD32 TIM3 CD4 DAP10 CD79a TIM3 CD4 DAP10 CD79b TIM3 CD4 DAP12 CD8TIM3 CD4 DAP12 CD3ζ TIM3 CD4 DAP12 CD3δ TIM3 CD4 DAP12 CD3γ TIM3 CD4DAP12 CD3ε TIM3 CD4 DAP12 FcγRI-γ TIM3 CD4 DAP12 FcγRIII-γ TIM3 CD4DAP12 FcεRIβ TIM3 CD4 DAP12 FcεRIγ TIM3 CD4 DAP12 DAP10 TIM3 CD4 DAP12DAP12 TIM3 CD4 DAP12 CD32 TIM3 CD4 DAP12 CD79a TIM3 CD4 DAP12 CD79b TIM3CD4 MyD88 CD8 TIM3 CD4 MyD88 CD3ζ TIM3 CD4 MyD88 CD3δ TIM3 CD4 MyD88CD3γ TIM3 CD4 MyD88 CD3ε TIM3 CD4 MyD88 FcγRI-γ TIM3 CD4 MyD88 FcγRIII-γTIM3 CD4 MyD88 FcεRIβ TIM3 CD4 MyD88 FcεRIγ TIM3 CD4 MyD88 DAP10 TIM3CD4 MyD88 DAP12 TIM3 CD4 MyD88 CD32 TIM3 CD4 MyD88 CD79a TIM3 CD4 MyD88CD79b TIM3 CD4 CD7 CD8 TIM3 CD4 CD7 CD3ζ TIM3 CD4 CD7 CD3δ TIM3 CD4 CD7CD3γ TIM3 CD4 CD7 CD3ε TIM3 CD4 CD7 FcγRI-γ TIM3 CD4 CD7 FcγRIII-γ TIM3CD4 CD7 FcεRIβ TIM3 CD4 CD7 FcεRIγ TIM3 CD4 CD7 DAP10 TIM3 CD4 CD7 DAP12TIM3 CD4 CD7 CD32 TIM3 CD4 CD7 CD79a TIM3 CD4 CD7 CD79b TIM3 CD4 BTNL3CD8 TIM3 CD4 BTNL3 CD3ζ TIM3 CD4 BTNL3 CD3δ TIM3 CD4 BTNL3 CD3γ TIM3 CD4BTNL3 CD3ε TIM3 CD4 BTNL3 FcγRI-γ TIM3 CD4 BTNL3 FcγRIII-γ TIM3 CD4BTNL3 FcεRIβ TIM3 CD4 BTNL3 FcεRIγ TIM3 CD4 BTNL3 DAP10 TIM3 CD4 BTNL3DAP12 TIM3 CD4 BTNL3 CD32 TIM3 CD4 BTNL3 CD79a TIM3 CD4 BTNL3 CD79b TIM3CD4 NKG2D CD8 TIM3 CD4 NKG2D CD3ζ TIM3 CD4 NKG2D CD3δ TIM3 CD4 NKG2DCD3γ TIM3 CD4 NKG2D CD3ε TIM3 CD4 NKG2D FcγRI-γ TIM3 CD4 NKG2D FcγRIII-γTIM3 CD4 NKG2D FcεRIβ TIM3 CD4 NKG2D FcεRIγ TIM3 CD4 NKG2D DAP10 TIM3CD4 NKG2D DAP12 TIM3 CD4 NKG2D CD32 TIM3 CD4 NKG2D CD79a TIM3 CD4 NKG2DCD79b TIM3 b2c CD28 CD8 TIM3 b2c CD28 CD3ζ TIM3 b2c CD28 CD3δ TIM3 b2cCD28 CD3γ TIM3 b2c CD28 CD3ε TIM3 b2c CD28 FcγRI-γ TIM3 b2c CD28FcγRIII-γ TIM3 b2c CD28 FcεRIβ TIM3 b2c CD28 FcεRIγ TIM3 b2c CD28 DAP10TIM3 b2c CD28 DAP12 TIM3 b2c CD28 CD32 TIM3 b2c CD28 CD79a TIM3 b2c CD28CD79b TIM3 b2c CD8 CD8 TIM3 b2c CD8 CD3ζ TIM3 b2c CD8 CD3δ TIM3 b2c CD8CD3γ TIM3 b2c CD8 CD3ε TIM3 b2c CD8 FcγRI-γ TIM3 b2c CD8 FcγRIII-γ TIM3b2c CD8 FcεRIβ TIM3 b2c CD8 FcεRIγ TIM3 b2c CD8 DAP10 TIM3 b2c CD8 DAP12TIM3 b2c CD8 CD32 TIM3 b2c CD8 CD79a TIM3 b2c CD8 CD79b TIM3 b2c CD4 CD8TIM3 b2c CD4 CD3ζ TIM3 b2c CD4 CD3δ TIM3 b2c CD4 CD3γ TIM3 b2c CD4 CD3εTIM3 b2c CD4 FcγRI-γ TIM3 b2c CD4 FcγRIII-γ TIM3 b2c CD4 FcεRIβ TIM3 b2cCD4 FcεRIγ TIM3 b2c CD4 DAP10 TIM3 b2c CD4 DAP12 TIM3 b2c CD4 CD32 TIM3b2c CD4 CD79a TIM3 b2c CD4 CD79b TIM3 b2c b2c CD8 TIM3 b2c b2c CD3ζ TIM3b2c b2c CD3δ TIM3 b2c b2c CD3γ TIM3 b2c b2c CD3ε TIM3 b2c b2c FcγRI-γTIM3 b2c b2c FcγRIII-γ TIM3 b2c b2c FcεRIβ TIM3 b2c b2c FcεRIγ TIM3 b2cb2c DAP10 TIM3 b2c b2c DAP12 TIM3 b2c b2c CD32 TIM3 b2c b2c CD79a TIM3b2c b2c CD79b TIM3 b2c CD137/41BB CD8 TIM3 b2c CD137/41BB CD3ζ TIM3 b2cCD137/41BB CD3δ TIM3 b2c CD137/41BB CD3γ TIM3 b2c CD137/41BB CD3ε TIM3b2c CD137/41BB FcγRI-γ TIM3 b2c CD137/41BB FcγRIII-γ TIM3 b2c CD137/41BBFcεRIβ TIM3 b2c CD137/41BB FcεRIγ TIM3 b2c CD137/41BB DAP10 TIM3 b2cCD137/41BB DAP12 TIM3 b2c CD137/41BB CD32 TIM3 b2c CD137/41BB CD79a TIM3b2c CD137/41BB CD79b TIM3 b2c ICOS CD8 TIM3 b2c ICOS CD3ζ TIM3 b2c ICOSCD3δ TIM3 b2c ICOS CD3γ TIM3 b2c ICOS CD3ε TIM3 b2c ICOS FcγRI-γ TIM3b2c ICOS FcγRIII-γ TIM3 b2c ICOS FcεRIβ TIM3 b2c ICOS FcεRIγ TIM3 b2cICOS DAP10 TIM3 b2c ICOS DAP12 TIM3 b2c ICOS CD32 TIM3 b2c ICOS CD79aTIM3 b2c ICOS CD79b TIM3 b2c CD27 CD8 TIM3 b2c CD27 CD3ζ TIM3 b2c CD27CD3δ TIM3 b2c CD27 CD3γ TIM3 b2c CD27 CD3ε TIM3 b2c CD27 FcγRI-γ TIM3b2c CD27 FcγRIII-γ TIM3 b2c CD27 FcεRIβ TIM3 b2c CD27 FcεRIγ TIM3 b2cCD27 DAP10 TIM3 b2c CD27 DAP12 TIM3 b2c CD27 CD32 TIM3 b2c CD27 CD79aTIM3 b2c CD27 CD79b TIM3 b2c CD28δ CD8 TIM3 b2c CD28δ CD3ζ TIM3 b2cCD28δ CD3δ TIM3 b2c CD28δ CD3γ TIM3 b2c CD28δ CD3ε TIM3 b2c CD28δFcγRI-γ TIM3 b2c CD28δ FcγRIII-γ TIM3 b2c CD28δ FcεRIβ TIM3 b2c CD28δFcεRIγ TIM3 b2c CD28δ DAP10 TIM3 b2c CD28δ DAP12 TIM3 b2c CD28δ CD32TIM3 b2c CD28δ CD79a TIM3 b2c CD28δ CD79b TIM3 b2c CD80 CD8 TIM3 b2cCD80 CD3ζ TIM3 b2c CD80 CD3δ TIM3 b2c CD80 CD3γ TIM3 b2c CD80 CD3ε TIM3b2c CD80 FcγRI-γ TIM3 b2c CD80 FcγRIII-γ TIM3 b2c CD80 FcεRIβ TIM3 b2cCD80 FcεRIγ TIM3 b2c CD80 DAP10 TIM3 b2c CD80 DAP12 TIM3 b2c CD80 CD32TIM3 b2c CD80 CD79a TIM3 b2c CD80 CD79b TIM3 b2c CD86 CD8 TIM3 b2c CD86CD3ζ TIM3 b2c CD86 CD3δ TIM3 b2c CD86 CD3γ TIM3 b2c CD86 CD3ε TIM3 b2cCD86 FcγRI-γ TIM3 b2c CD86 FcγRIII-γ TIM3 b2c CD86 FcεRIβ TIM3 b2c CD86FcεRIγ TIM3 b2c CD86 DAP10 TIM3 b2c CD86 DAP12 TIM3 b2c CD86 CD32 TIM3b2c CD86 CD79a TIM3 b2c CD86 CD79b TIM3 b2c OX40 CD8 TIM3 b2c OX40 CD3ζTIM3 b2c OX40 CD3δ TIM3 b2c OX40 CD3γ TIM3 b2c OX40 CD3ε TIM3 b2c OX40FcγRI-γ TIM3 b2c OX40 FcγRIII-γ TIM3 b2c OX40 FcεRIβ TIM3 b2c OX40FcεRIγ TIM3 b2c OX40 DAP10 TIM3 b2c OX40 DAP12 TIM3 b2c OX40 CD32 TIM3b2c OX40 CD79a TIM3 b2c OX40 CD79b TIM3 b2c DAP10 CD8 TIM3 b2c DAP10CD3ζ TIM3 b2c DAP10 CD3δ TIM3 b2c DAP10 CD3γ TIM3 b2c DAP10 CD3ε TIM3b2c DAP10 FcγRI-γ TIM3 b2c DAP10 FcγRIII-γ TIM3 b2c DAP10 FcεRIβ TIM3b2c DAP10 FcεRIγ TIM3 b2c DAP10 DAP10 TIM3 b2c DAP10 DAP12 TIM3 b2cDAP10 CD32 TIM3 b2c DAP10 CD79a TIM3 b2c DAP10 CD79b TIM3 b2c DAP12 CD8TIM3 b2c DAP12 CD3ζ TIM3 b2c DAP12 CD3δ TIM3 b2c DAP12 CD3γ TIM3 b2cDAP12 CD3ε TIM3 b2c DAP12 FcγRI-γ TIM3 b2c DAP12 FcγRIII-γ TIM3 b2cDAP12 FcεRIβ TIM3 b2c DAP12 FcεRIγ TIM3 b2c DAP12 DAP10 TIM3 b2c DAP12DAP12 TIM3 b2c DAP12 CD32 TIM3 b2c DAP12 CD79a TIM3 b2c DAP12 CD79b TIM3b2c MyD88 CD8 TIM3 b2c MyD88 CD3ζ TIM3 b2c MyD88 CD3δ TIM3 b2c MyD88CD3γ TIM3 b2c MyD88 CD3ε TIM3 b2c MyD88 FcγRI-γ TIM3 b2c MyD88 FcγRIII-γTIM3 b2c MyD88 FcεRIβ TIM3 b2c MyD88 FcεRIγ TIM3 b2c MyD88 DAP10 TIM3b2c MyD88 DAP12 TIM3 b2c MyD88 CD32 TIM3 b2c MyD88 CD79a TIM3 b2c MyD88CD79b TIM3 b2c CD7 CD8 TIM3 b2c CD7 CD3ζ TIM3 b2c CD7 CD3δ TIM3 b2c CD7CD3γ TIM3 b2c CD7 CD3ε TIM3 b2c CD7 FcγRI-γ TIM3 b2c CD7 FcγRIII-γ TIM3b2c CD7 FcεRIβ TIM3 b2c CD7 FcεRIγ TIM3 b2c CD7 DAP10 TIM3 b2c CD7 DAP12TIM3 b2c CD7 CD32 TIM3 b2c CD7 CD79a TIM3 b2c CD7 CD79b TIM3 b2c BTNL3CD8 TIM3 b2c BTNL3 CD3ζ TIM3 b2c BTNL3 CD3δ TIM3 b2c BTNL3 CD3γ TIM3 b2cBTNL3 CD3ε TIM3 b2c BTNL3 FcγRI-γ TIM3 b2c BTNL3 FcγRIII-γ TIM3 b2cBTNL3 FcεRIβ TIM3 b2c BTNL3 FcεRIγ TIM3 b2c BTNL3 DAP10 TIM3 b2c BTNL3DAP12 TIM3 b2c BTNL3 CD32 TIM3 b2c BTNL3 CD79a TIM3 b2c BTNL3 CD79b TIM3b2c NKG2D CD8 TIM3 b2c NKG2D CD3ζ TIM3 b2c NKG2D CD3δ TIM3 b2c NKG2DCD3γ TIM3 b2c NKG2D CD3ε TIM3 b2c NKG2D FcγRI-γ TIM3 b2c NKG2D FcγRIII-γTIM3 b2c NKG2D FcεRIβ TIM3 b2c NKG2D FcεRIγ TIM3 b2c NKG2D DAP10 TIM3b2c NKG2D DAP12 TIM3 b2c NKG2D CD32 TIM3 b2c NKG2D CD79a TIM3 b2c NKG2DCD79b TIM3 CD137/41BB CD28 CD8 TIM3 CD137/41BB CD28 CD3ζ TIM3 CD137/41BBCD28 CD3δ TIM3 CD137/41BB CD28 CD3γ TIM3 CD137/41BB CD28 CD3ε TIM3CD137/41BB CD28 FcγRI-γ TIM3 CD137/41BB CD28 FcγRIII-γ TIM3 CD137/41BBCD28 FcεRIβ TIM3 CD137/41BB CD28 FcεRIγ TIM3 CD137/41BB CD28 DAP10 TIM3CD137/41BB CD28 DAP12 TIM3 CD137/41BB CD28 CD32 TIM3 CD137/41BB CD28CD79a TIM3 CD137/41BB CD28 CD79b TIM3 CD137/41BB CD8 CD8 TIM3 CD137/41BBCD8 CD3ζ TIM3 CD137/41BB CD8 CD3δ TIM3 CD137/41BB CD8 CD3γ TIM3CD137/41BB CD8 CD3ε TIM3 CD137/41BB CD8 FcγRI-γ TIM3 CD137/41BB CD8FcγRIII-γ TIM3 CD137/41BB CD8 FcεRIβ TIM3 CD137/41BB CD8 FcεRIγ TIM3CD137/41BB CD8 DAP10 TIM3 CD137/41BB CD8 DAP12 TIM3 CD137/41BB CD8 CD32TIM3 CD137/41BB CD8 CD79a TIM3 CD137/41BB CD8 CD79b TIM3 CD137/41BB CD4CD8 TIM3 CD137/41BB CD4 CD3ζ TIM3 CD137/41BB CD4 CD3δ TIM3 CD137/41BBCD4 CD3γ TIM3 CD137/41BB CD4 CD3ε TIM3 CD137/41BB CD4 FcγRI-γ TIM3CD137/41BB CD4 FcγRIII-γ TIM3 CD137/41BB CD4 FcεRIβ TIM3 CD137/41BB CD4FcεRIγ TIM3 CD137/41BB CD4 DAP10 TIM3 CD137/41BB CD4 DAP12 TIM3CD137/41BB CD4 CD32 TIM3 CD137/41BB CD4 CD79a TIM3 CD137/41BB CD4 CD79bTIM3 CD137/41BB b2c CD8 TIM3 CD137/41BB b2c CD3ζ TIM3 CD137/41BB b2cCD3δ TIM3 CD137/41BB b2c CD3γ TIM3 CD137/41BB b2c CD3ε TIM3 CD137/41BBb2c FcγRI-γ TIM3 CD137/41BB b2c FcγRIII-γ TIM3 CD137/41BB b2c FcεRIβTIM3 CD137/41BB b2c FcεRIγ TIM3 CD137/41BB b2c DAP10 TIM3 CD137/41BB b2cDAP12 TIM3 CD137/41BB b2c CD32 TIM3 CD137/41BB b2c CD79a TIM3 CD137/41BBb2c CD79b TIM3 CD137/41BB CD137/41BB CD8 TIM3 CD137/41BB CD137/41BB CD3ζTIM3 CD137/41BB CD137/41BB CD3δ TIM3 CD137/41BB CD137/41BB CD3γ TIM3CD137/41BB CD137/41BB CD3ε TIM3 CD137/41BB CD137/41BB FcγRI-γ TIM3CD137/41BB CD137/41BB FcγRIII-γ TIM3 CD137/41BB CD137/41BB FcεRIβ TIM3CD137/41BB CD137/41BB FcεRIγ TIM3 CD137/41BB CD137/41BB DAP10 TIM3CD137/41BB CD137/41BB DAP12 TIM3 CD137/41BB CD137/41BB CD32 TIM3CD137/41BB CD137/41BB CD79a TIM3 CD137/41BB CD137/41BB CD79b TIM3CD137/41BB ICOS CD8 TIM3 CD137/41BB ICOS CD3ζ TIM3 CD137/41BB ICOS CD3δTIM3 CD137/41BB ICOS CD3γ TIM3 CD137/41BB ICOS CD3ε TIM3 CD137/41BB ICOSFcγRI-γ TIM3 CD137/41BB ICOS FcγRIII-γ TIM3 CD137/41BB ICOS FcεRIβ TIM3CD137/41BB ICOS FcεRIγ TIM3 CD137/41BB ICOS DAP10 TIM3 CD137/41BB ICOSDAP12 TIM3 CD137/41BB ICOS CD32 TIM3 CD137/41BB ICOS CD79a TIM3CD137/41BB ICOS CD79b TIM3 CD137/41BB CD27 CD8 TIM3 CD137/41BB CD27 CD3ζTIM3 CD137/41BB CD27 CD3δ TIM3 CD137/41BB CD27 CD3γ TIM3 CD137/41BB CD27CD3ε TIM3 CD137/41BB CD27 FcγRI-γ TIM3 CD137/41BB CD27 FcγRIII-γ TIM3CD137/41BB CD27 FcεRIβ TIM3 CD137/41BB CD27 FcεRIγ TIM3 CD137/41BB CD27DAP10 TIM3 CD137/41BB CD27 DAP12 TIM3 CD137/41BB CD27 CD32 TIM3CD137/41BB CD27 CD79a TIM3 CD137/41BB CD27 CD79b TIM3 CD137/41BB CD28δCD8 TIM3 CD137/41BB CD28δ CD3ζ TIM3 CD137/41BB CD28δ CD3δ TIM3CD137/41BB CD28δ CD3γ TIM3 CD137/41BB CD28δ CD3ε TIM3 CD137/41BB CD28δFcγRI-γ TIM3 CD137/41BB CD28δ FcγRIII-γ TIM3 CD137/41BB CD28δ FcεRIβTIM3 CD137/41BB CD28δ FcεRIγ TIM3 CD137/41BB CD28δ DAP10 TIM3 CD137/41BBCD28δ DAP12 TIM3 CD137/41BB CD28δ CD32 TIM3 CD137/41BB CD28δ CD79a TIM3CD137/41BB CD28δ CD79b TIM3 CD137/41BB CD80 CD8 TIM3 CD137/41BB CD80CD3ζ TIM3 CD137/41BB CD80 CD3δ TIM3 CD137/41BB CD80 CD3γ TIM3 CD137/41BBCD80 CD3ε TIM3 CD137/41BB CD80 FcγRI-γ TIM3 CD137/41BB CD80 FcγRIII-γTIM3 CD137/41BB CD80 FcεRIβ TIM3 CD137/41BB CD80 FcεRIγ TIM3 CD137/41BBCD80 DAP10 TIM3 CD137/41BB CD80 DAP12 TIM3 CD137/41BB CD80 CD32 TIM3CD137/41BB CD80 CD79a TIM3 CD137/41BB CD80 CD79b TIM3 CD137/41BB CD86CD8 TIM3 CD137/41BB CD86 CD3ζ TIM3 CD137/41BB CD86 CD3δ TIM3 CD137/41BBCD86 CD3γ TIM3 CD137/41BB CD86 CD3ε TIM3 CD137/41BB CD86 FcγRI-γ TIM3CD137/41BB CD86 FcγRIII-γ TIM3 CD137/41BB CD86 FcεRIβ TIM3 CD137/41BBCD86 FcεRIγ TIM3 CD137/41BB CD86 DAP10 TIM3 CD137/41BB CD86 DAP12 TIM3CD137/41BB CD86 CD32 TIM3 CD137/41BB CD86 CD79a TIM3 CD137/41BB CD86CD79b TIM3 CD137/41BB OX40 CD8 TIM3 CD137/41BB OX40 CD3ζ TIM3 CD137/41BBOX40 CD3δ TIM3 CD137/41BB OX40 CD3γ TIM3 CD137/41BB OX40 CD3ε TIM3CD137/41BB OX40 FcγRI-γ TIM3 CD137/41BB OX40 FcγRIII-γ TIM3 CD137/41BBOX40 FcεRIβ TIM3 CD137/41BB OX40 FcεRIγ TIM3 CD137/41BB OX40 DAP10 TIM3CD137/41BB OX40 DAP12 TIM3 CD137/41BB OX40 CD32 TIM3 CD137/41BB OX40CD79a TIM3 CD137/41BB OX40 CD79b TIM3 CD137/41BB DAP10 CD8 TIM3CD137/41BB DAP10 CD3ζ TIM3 CD137/41BB DAP10 CD3δ TIM3 CD137/41BB DAP10CD3γ TIM3 CD137/41BB DAP10 CD3ε TIM3 CD137/41BB DAP10 FcγRI-γ TIM3CD137/41BB DAP10 FcγRIII-γ TIM3 CD137/41BB DAP10 FcεRIβ TIM3 CD137/41BBDAP10 FcεRIγ TIM3 CD137/41BB DAP10 DAP10 TIM3 CD137/41BB DAP10 DAP12TIM3 CD137/41BB DAP10 CD32 TIM3 CD137/41BB DAP10 CD79a TIM3 CD137/41BBDAP10 CD79b TIM3 CD137/41BB DAP12 CD8 TIM3 CD137/41BB DAP12 CD3ζ TIM3CD137/41BB DAP12 CD3δ TIM3 CD137/41BB DAP12 CD3γ TIM3 CD137/41BB DAP12CD3ε TIM3 CD137/41BB DAP12 FcγRI-γ TIM3 CD137/41BB DAP12 FcγRIII-γ TIM3CD137/41BB DAP12 FcεRIβ TIM3 CD137/41BB DAP12 FcεRIγ TIM3 CD137/41BBDAP12 DAP10 TIM3 CD137/41BB DAP12 DAP12 TIM3 CD137/41BB DAP12 CD32 TIM3CD137/41BB DAP12 CD79a TIM3 CD137/41BB DAP12 CD79b TIM3 CD137/41BB MyD88CD8 TIM3 CD137/41BB MyD88 CD3ζ TIM3 CD137/41BB MyD88 CD3δ TIM3CD137/41BB MyD88 CD3γ TIM3 CD137/41BB MyD88 CD3ε TIM3 CD137/41BB MyD88FcγRI-γ TIM3 CD137/41BB MyD88 FcγRIII-γ TIM3 CD137/41BB MyD88 FcεRIβTIM3 CD137/41BB MyD88 FcεRIγ TIM3 CD137/41BB MyD88 DAP10 TIM3 CD137/41BBMyD88 DAP12 TIM3 CD137/41BB MyD88 CD32 TIM3 CD137/41BB MyD88 CD79a TIM3CD137/41BB MyD88 CD79b TIM3 CD137/41BB CD7 CD8 TIM3 CD137/41BB CD7 CD3ζTIM3 CD137/41BB CD7 CD3δ TIM3 CD137/41BB CD7 CD3γ TIM3 CD137/41BB CD7CD3ε TIM3 CD137/41BB CD7 FcγRI-γ TIM3 CD137/41BB CD7 FcγRIII-γ TIM3CD137/41BB CD7 FcεRIβ TIM3 CD137/41BB CD7 FcεRIγ TIM3 CD137/41BB CD7DAP10 TIM3 CD137/41BB CD7 DAP12 TIM3 CD137/41BB CD7 CD32 TIM3 CD137/41BBCD7 CD79a TIM3 CD137/41BB CD7 CD79b TIM3 CD137/41BB BTNL3 CD8 TIM3CD137/41BB BTNL3 CD3ζ TIM3 CD137/41BB BTNL3 CD3δ TIM3 CD137/41BB BTNL3CD3γ TIM3 CD137/41BB BTNL3 CD3ε TIM3 CD137/41BB BTNL3 FcγRI-γ TIM3CD137/41BB BTNL3 FcγRIII-γ TIM3 CD137/41BB BTNL3 FcεRIβ TIM3 CD137/41BBBTNL3 FcεRIγ TIM3 CD137/41BB BTNL3 DAP10 TIM3 CD137/41BB BTNL3 DAP12TIM3 CD137/41BB BTNL3 CD32 TIM3 CD137/41BB BTNL3 CD79a TIM3 CD137/41BBBTNL3 CD79b TIM3 CD137/41BB NKG2D CD8 TIM3 CD137/41BB NKG2D CD3ζ TIM3CD137/41BB NKG2D CD3δ TIM3 CD137/41BB NKG2D CD3γ TIM3 CD137/41BB NKG2DCD3ε TIM3 CD137/41BB NKG2D FcγRI-γ TIM3 CD137/41BB NKG2D FcγRIII-γ TIM3CD137/41BB NKG2D FcεRIβ TIM3 CD137/41BB NKG2D FcεRIγ TIM3 CD137/41BBNKG2D DAP10 TIM3 CD137/41BB NKG2D DAP12 TIM3 CD137/41BB NKG2D CD32 TIM3CD137/41BB NKG2D CD79a TIM3 CD137/41BB NKG2D CD79b TIM3 ICOS CD28 CD8TIM3 ICOS CD28 CD3ζ TIM3 ICOS CD28 CD3δ TIM3 ICOS CD28 CD3γ TIM3 ICOSCD28 CD3ε TIM3 ICOS CD28 FcγRI-γ TIM3 ICOS CD28 FcγRIII-γ TIM3 ICOS CD28FcεRIβ TIM3 ICOS CD28 FcεRIγ TIM3 ICOS CD28 DAP10 TIM3 ICOS CD28 DAP12TIM3 ICOS CD28 CD32 TIM3 ICOS CD28 CD79a TIM3 ICOS CD28 CD79b TIM3 ICOSCD8 CD8 TIM3 ICOS CD8 CD3ζ TIM3 ICOS CD8 CD3δ TIM3 ICOS CD8 CD3γ TIM3ICOS CD8 CD3ε TIM3 ICOS CD8 FcγRI-γ TIM3 ICOS CD8 FcγRIII-γ TIM3 ICOSCD8 FcεRIβ TIM3 ICOS CD8 FcεRIγ TIM3 ICOS CD8 DAP10 TIM3 ICOS CD8 DAP12TIM3 ICOS CD8 CD32 TIM3 ICOS CD8 CD79a TIM3 ICOS CD8 CD79b TIM3 ICOS CD4CD8 TIM3 ICOS CD4 CD3ζ TIM3 ICOS CD4 CD3δ TIM3 ICOS CD4 CD3γ TIM3 ICOSCD4 CD3ε TIM3 ICOS CD4 FcγRI-γ TIM3 ICOS CD4 FcγRIII-γ TIM3 ICOS CD4FcεRIβ TIM3 ICOS CD4 FcεRIγ TIM3 ICOS CD4 DAP10 TIM3 ICOS CD4 DAP12 TIM3ICOS CD4 CD32 TIM3 ICOS CD4 CD79a TIM3 ICOS CD4 CD79b TIM3 ICOS b2c CD8TIM3 ICOS b2c CD3ζ TIM3 ICOS b2c CD3δ TIM3 ICOS b2c CD3γ TIM3 ICOS b2cCD3ε TIM3 ICOS b2c FcγRI-γ TIM3 ICOS b2c FcγRIII-γ TIM3 ICOS b2c FcεRIβTIM3 ICOS b2c FcεRIγ TIM3 ICOS b2c DAP10 TIM3 ICOS b2c DAP12 TIM3 ICOSb2c CD32 TIM3 ICOS b2c CD79a TIM3 ICOS b2c CD79b TIM3 ICOS CD137/41BBCD8 TIM3 ICOS CD137/41BB CD3ζ TIM3 ICOS CD137/41BB CD3δ TIM3 ICOSCD137/41BB CD3γ TIM3 ICOS CD137/41BB CD3ε TIM3 ICOS CD137/41BB FcγRI-γTIM3 ICOS CD137/41BB FcγRIII-γ TIM3 ICOS CD137/41BB FcεRIβ TIM3 ICOSCD137/41BB FcεRIγ TIM3 ICOS CD137/41BB DAP10 TIM3 ICOS CD137/41BB DAP12TIM3 ICOS CD137/41BB CD32 TIM3 ICOS CD137/41BB CD79a TIM3 ICOSCD137/41BB CD79b TIM3 ICOS ICOS CD8 TIM3 ICOS ICOS CD3ζ TIM3 ICOS ICOSCD3δ TIM3 ICOS ICOS CD3γ TIM3 ICOS ICOS CD3ε TIM3 ICOS ICOS FcγRI-γ TIM3ICOS ICOS FcγRIII-γ TIM3 ICOS ICOS FcεRIβ TIM3 ICOS ICOS FcεRIγ TIM3ICOS ICOS DAP10 TIM3 ICOS ICOS DAP12 TIM3 ICOS ICOS CD32 TIM3 ICOS ICOSCD79a TIM3 ICOS ICOS CD79b TIM3 ICOS CD27 CD8 TIM3 ICOS CD27 CD3ζ TIM3ICOS CD27 CD3δ TIM3 ICOS CD27 CD3γ TIM3 ICOS CD27 CD3ε TIM3 ICOS CD27FcγRI-γ TIM3 ICOS CD27 FcγRIII-γ TIM3 ICOS CD27 FcεRIβ TIM3 ICOS CD27FcεRIγ TIM3 ICOS CD27 DAP10 TIM3 ICOS CD27 DAP12 TIM3 ICOS CD27 CD32TIM3 ICOS CD27 CD79a TIM3 ICOS CD27 CD79b TIM3 ICOS CD28δ CD8 TIM3 ICOSCD28δ CD3ζ TIM3 ICOS CD28δ CD3δ TIM3 ICOS CD28δ CD3γ TIM3 ICOS CD28δCD3ε TIM3 ICOS CD28δ FcγRI-γ TIM3 ICOS CD28δ FcγRIII-γ TIM3 ICOS CD28δFcεRIβ TIM3 ICOS CD28δ FcεRIγ TIM3 ICOS CD28δ DAP10 TIM3 ICOS CD28δDAP12 TIM3 ICOS CD28δ CD32 TIM3 ICOS CD28δ CD79a TIM3 ICOS CD28δ CD79bTIM3 ICOS CD80 CD8 TIM3 ICOS CD80 CD3ζ TIM3 ICOS CD80 CD3δ TIM3 ICOSCD80 CD3γ TIM3 ICOS CD80 CD3ε TIM3 ICOS CD80 FcγRI-γ TIM3 ICOS CD80FcγRIII-γ TIM3 ICOS CD80 FcεRIβ TIM3 ICOS CD80 FcεRIγ TIM3 ICOS CD80DAP10 TIM3 ICOS CD80 DAP12 TIM3 ICOS CD80 CD32 TIM3 ICOS CD80 CD79a TIM3ICOS CD80 CD79b TIM3 ICOS CD86 CD8 TIM3 ICOS CD86 CD3ζ TIM3 ICOS CD86CD3δ TIM3 ICOS CD86 CD3γ TIM3 ICOS CD86 CD3ε TIM3 ICOS CD86 FcγRI-γ TIM3ICOS CD86 FcγRIII-γ TIM3 ICOS CD86 FcεRIβ TIM3 ICOS CD86 FcεRIγ TIM3ICOS CD86 DAP10 TIM3 ICOS CD86 DAP12 TIM3 ICOS CD86 CD32 TIM3 ICOS CD86CD79a TIM3 ICOS CD86 CD79b TIM3 ICOS OX40 CD8 TIM3 ICOS OX40 CD3ζ TIM3ICOS OX40 CD3δ TIM3 ICOS OX40 CD3γ TIM3 ICOS OX40 CD3ε TIM3 ICOS OX40FcγRI-γ TIM3 ICOS OX40 FcγRIII-γ TIM3 ICOS OX40 FcεRIβ TIM3 ICOS OX40FcεRIγ TIM3 ICOS OX40 DAP10 TIM3 ICOS OX40 DAP12 TIM3 ICOS OX40 CD32TIM3 ICOS OX40 CD79a TIM3 ICOS OX40 CD79b TIM3 ICOS DAP10 CD8 TIM3 ICOSDAP10 CD3ζ TIM3 ICOS DAP10 CD3δ TIM3 ICOS DAP10 CD3γ TIM3 ICOS DAP10CD3ε TIM3 ICOS DAP10 FcγRI-γ TIM3 ICOS DAP10 FcγRIII-γ TIM3 ICOS DAP10FcεRIβ TIM3 ICOS DAP10 FcεRIγ TIM3 ICOS DAP10 DAP10 TIM3 ICOS DAP10DAP12 TIM3 ICOS DAP10 CD32 TIM3 ICOS DAP10 CD79a TIM3 ICOS DAP10 CD79bTIM3 ICOS DAP12 CD8 TIM3 ICOS DAP12 CD3ζ TIM3 ICOS DAP12 CD3δ TIM3 ICOSDAP12 CD3γ TIM3 ICOS DAP12 CD3ε TIM3 ICOS DAP12 FcγRI-γ TIM3 ICOS DAP12FcγRIII-γ TIM3 ICOS DAP12 FcεRIβ TIM3 ICOS DAP12 FcεRIγ TIM3 ICOS DAP12DAP10 TIM3 ICOS DAP12 DAP12 TIM3 ICOS DAP12 CD32 TIM3 ICOS DAP12 CD79aTIM3 ICOS DAP12 CD79b TIM3 ICOS MyD88 CD8 TIM3 ICOS MyD88 CD3ζ TIM3 ICOSMyD88 CD3δ TIM3 ICOS MyD88 CD3γ TIM3 ICOS MyD88 CD3ε TIM3 ICOS MyD88FcγRI-γ TIM3 ICOS MyD88 FcγRIII-γ TIM3 ICOS MyD88 FcεRIβ TIM3 ICOS MyD88FcεRIγ TIM3 ICOS MyD88 DAP10 TIM3 ICOS MyD88 DAP12 TIM3 ICOS MyD88 CD32TIM3 ICOS MyD88 CD79a TIM3 ICOS MyD88 CD79b TIM3 ICOS CD7 CD8 TIM3 ICOSCD7 CD3ζ TIM3 ICOS CD7 CD3δ TIM3 ICOS CD7 CD3γ TIM3 ICOS CD7 CD3ε TIM3ICOS CD7 FcγRI-γ TIM3 ICOS CD7 FcγRIII-γ TIM3 ICOS CD7 FcεRIβ TIM3 ICOSCD7 FcεRIγ TIM3 ICOS CD7 DAP10 TIM3 ICOS CD7 DAP12 TIM3 ICOS CD7 CD32TIM3 ICOS CD7 CD79a TIM3 ICOS CD7 CD79b TIM3 ICOS BTNL3 CD8 TIM3 ICOSBTNL3 CD3ζ TIM3 ICOS BTNL3 CD3δ TIM3 ICOS BTNL3 CD3γ TIM3 ICOS BTNL3CD3ε TIM3 ICOS BTNL3 FcγRI-γ TIM3 ICOS BTNL3 FcγRIII-γ TIM3 ICOS BTNL3FcεRIβ TIM3 ICOS BTNL3 FcεRIγ TIM3 ICOS BTNL3 DAP10 TIM3 ICOS BTNL3DAP12 TIM3 ICOS BTNL3 CD32 TIM3 ICOS BTNL3 CD79a TIM3 ICOS BTNL3 CD79bTIM3 ICOS NKG2D CD8 TIM3 ICOS NKG2D CD3ζ TIM3 ICOS NKG2D CD3δ TIM3 ICOSNKG2D CD3γ TIM3 ICOS NKG2D CD3ε TIM3 ICOS NKG2D FcγRI-γ TIM3 ICOS NKG2DFcγRIII-γ TIM3 ICOS NKG2D FcεRIβ TIM3 ICOS NKG2D FcεRIγ TIM3 ICOS NKG2DDAP10 TIM3 ICOS NKG2D DAP12 TIM3 ICOS NKG2D CD32 TIM3 ICOS NKG2D CD79aTIM3 ICOS NKG2D CD79b TIM3 CD27 CD28 CD8 TIM3 CD27 CD28 CD3ζ TIM3 CD27CD28 CD3δ TIM3 CD27 CD28 CD3γ TIM3 CD27 CD28 CD3ε TIM3 CD27 CD28 FcγRI-γTIM3 CD27 CD28 FcγRIII-γ TIM3 CD27 CD28 FcεRIβ TIM3 CD27 CD28 FcεRIγTIM3 CD27 CD28 DAP10 TIM3 CD27 CD28 DAP12 TIM3 CD27 CD28 CD32 TIM3 CD27CD28 CD79a TIM3 CD27 CD28 CD79b TIM3 CD27 CD8 CD8 TIM3 CD27 CD8 CD3ζTIM3 CD27 CD8 CD3δ TIM3 CD27 CD8 CD3γ TIM3 CD27 CD8 CD3ε TIM3 CD27 CD8FcγRI-γ TIM3 CD27 CD8 FcγRIII-γ TIM3 CD27 CD8 FcεRIβ TIM3 CD27 CD8FcεRIγ TIM3 CD27 CD8 DAP10 TIM3 CD27 CD8 DAP12 TIM3 CD27 CD8 CD32 TIM3CD27 CD8 CD79a TIM3 CD27 CD8 CD79b TIM3 CD27 CD4 CD8 TIM3 CD27 CD4 CD3ζTIM3 CD27 CD4 CD3δ TIM3 CD27 CD4 CD3γ TIM3 CD27 CD4 CD3ε TIM3 CD27 CD4FcγRI-γ TIM3 CD27 CD4 FcγRIII-γ TIM3 CD27 CD4 FcεRIβ TIM3 CD27 CD4FcεRIγ TIM3 CD27 CD4 DAP10 TIM3 CD27 CD4 DAP12 TIM3 CD27 CD4 CD32 TIM3CD27 CD4 CD79a TIM3 CD27 CD4 CD79b TIM3 CD27 b2c CD8 TIM3 CD27 b2c CD3ζTIM3 CD27 b2c CD3δ TIM3 CD27 b2c CD3γ TIM3 CD27 b2c CD3ε TIM3 CD27 b2cFcγRI-γ TIM3 CD27 b2c FcγRIII-γ TIM3 CD27 b2c FcεRIβ TIM3 CD27 b2cFcεRIγ TIM3 CD27 b2c DAP10 TIM3 CD27 b2c DAP12 TIM3 CD27 b2c CD32 TIM3CD27 b2c CD79a TIM3 CD27 b2c CD79b TIM3 CD27 CD137/41BB CD8 TIM3 CD27CD137/41BB CD3ζ TIM3 CD27 CD137/41BB CD3δ TIM3 CD27 CD137/41BB CD3γ TIM3CD27 CD137/41BB CD3ε TIM3 CD27 CD137/41BB FcγRI-γ TIM3 CD27 CD137/41BBFcγRIII-γ TIM3 CD27 CD137/41BB FcεRIβ TIM3 CD27 CD137/41BB FcεRIγ TIM3CD27 CD137/41BB DAP10 TIM3 CD27 CD137/41BB DAP12 TIM3 CD27 CD137/41BBCD32 TIM3 CD27 CD137/41BB CD79a TIM3 CD27 CD137/41BB CD79b TIM3 CD27ICOS CD8 TIM3 CD27 ICOS CD3ζ TIM3 CD27 ICOS CD3δ TIM3 CD27 ICOS CD3γTIM3 CD27 ICOS CD3ε TIM3 CD27 ICOS FcγRI-γ TIM3 CD27 ICOS FcγRIII-γ TIM3CD27 ICOS FcεRIβ TIM3 CD27 ICOS FcεRIγ TIM3 CD27 ICOS DAP10 TIM3 CD27ICOS DAP12 TIM3 CD27 ICOS CD32 TIM3 CD27 ICOS CD79a TIM3 CD27 ICOS CD79bTIM3 CD27 CD27 CD8 TIM3 CD27 CD27 CD3ζ TIM3 CD27 CD27 CD3δ TIM3 CD27CD27 CD3γ TIM3 CD27 CD27 CD3ε TIM3 CD27 CD27 FcγRI-γ TIM3 CD27 CD27FcγRIII-γ TIM3 CD27 CD27 FcεRIβ TIM3 CD27 CD27 FcεRIγ TIM3 CD27 CD27DAP10 TIM3 CD27 CD27 DAP12 TIM3 CD27 CD27 CD32 TIM3 CD27 CD27 CD79a TIM3CD27 CD27 CD79b TIM3 CD27 CD28δ CD8 TIM3 CD27 CD28δ CD3ζ TIM3 CD27 CD28δCD3δ TIM3 CD27 CD28δ CD3γ TIM3 CD27 CD28δ CD3ε TIM3 CD27 CD28δ FcγRI-γTIM3 CD27 CD28δ FcγRIII-γ TIM3 CD27 CD28δ FcεRIβ TIM3 CD27 CD28δ FcεRIγTIM3 CD27 CD28δ DAP10 TIM3 CD27 CD28δ DAP12 TIM3 CD27 CD28δ CD32 TIM3CD27 CD28δ CD79a TIM3 CD27 CD28δ CD79b TIM3 CD27 CD80 CD8 TIM3 CD27 CD80CD3ζ TIM3 CD27 CD80 CD3δ TIM3 CD27 CD80 CD3γ TIM3 CD27 CD80 CD3ε TIM3CD27 CD80 FcγRI-γ TIM3 CD27 CD80 FcγRIII-γ TIM3 CD27 CD80 FcεRIβ TIM3CD27 CD80 FcεRIγ TIM3 CD27 CD80 DAP10 TIM3 CD27 CD80 DAP12 TIM3 CD27CD80 CD32 TIM3 CD27 CD80 CD79a TIM3 CD27 CD80 CD79b TIM3 CD27 CD86 CD8TIM3 CD27 CD86 CD3ζ TIM3 CD27 CD86 CD3δ TIM3 CD27 CD86 CD3γ TIM3 CD27CD86 CD3ε TIM3 CD27 CD86 FcγRI-γ TIM3 CD27 CD86 FcγRIII-γ TIM3 CD27 CD86FcεRIβ TIM3 CD27 CD86 FcεRIγ TIM3 CD27 CD86 DAP10 TIM3 CD27 CD86 DAP12TIM3 CD27 CD86 CD32 TIM3 CD27 CD86 CD79a TIM3 CD27 CD86 CD79b TIM3 CD27OX40 CD8 TIM3 CD27 OX40 CD3ζ TIM3 CD27 OX40 CD3δ TIM3 CD27 OX40 CD3γTIM3 CD27 OX40 CD3ε TIM3 CD27 OX40 FcγRI-γ TIM3 CD27 OX40 FcγRIII-γ TIM3CD27 OX40 FcεRIβ TIM3 CD27 OX40 FcεRIγ TIM3 CD27 OX40 DAP10 TIM3 CD27OX40 DAP12 TIM3 CD27 OX40 CD32 TIM3 CD27 OX40 CD79a TIM3 CD27 OX40 CD79bTIM3 CD27 DAP10 CD8 TIM3 CD27 DAP10 CD3ζ TIM3 CD27 DAP10 CD3δ TIM3 CD27DAP10 CD3γ TIM3 CD27 DAP10 CD3ε TIM3 CD27 DAP10 FcγRI-γ TIM3 CD27 DAP10FcγRIII-γ TIM3 CD27 DAP10 FcεRIβ TIM3 CD27 DAP10 FcεRIγ TIM3 CD27 DAP10DAP10 TIM3 CD27 DAP10 DAP12 TIM3 CD27 DAP10 CD32 TIM3 CD27 DAP10 CD79aTIM3 CD27 DAP10 CD79b TIM3 CD27 DAP12 CD8 TIM3 CD27 DAP12 CD3ζ TIM3 CD27DAP12 CD3δ TIM3 CD27 DAP12 CD3γ TIM3 CD27 DAP12 CD3ε TIM3 CD27 DAP12FcγRI-γ TIM3 CD27 DAP12 FcγRIII-γ TIM3 CD27 DAP12 FcεRIβ TIM3 CD27 DAP12FcεRIγ TIM3 CD27 DAP12 DAP10 TIM3 CD27 DAP12 DAP12 TIM3 CD27 DAP12 CD32TIM3 CD27 DAP12 CD79a TIM3 CD27 DAP12 CD79b TIM3 CD27 MyD88 CD8 TIM3CD27 MyD88 CD3ζ TIM3 CD27 MyD88 CD3δ TIM3 CD27 MyD88 CD3γ TIM3 CD27MyD88 CD3ε TIM3 CD27 MyD88 FcγRI-γ TIM3 CD27 MyD88 FcγRIII-γ TIM3 CD27MyD88 FcεRIβ TIM3 CD27 MyD88 FcεRIγ TIM3 CD27 MyD88 DAP10 TIM3 CD27MyD88 DAP12 TIM3 CD27 MyD88 CD32 TIM3 CD27 MyD88 CD79a TIM3 CD27 MyD88CD79b TIM3 CD27 CD7 CD8 TIM3 CD27 CD7 CD3ζ TIM3 CD27 CD7 CD3δ TIM3 CD27CD7 CD3γ TIM3 CD27 CD7 CD3ε TIM3 CD27 CD7 FcγRI-γ TIM3 CD27 CD7FcγRIII-γ TIM3 CD27 CD7 FcεRIβ TIM3 CD27 CD7 FcεRIγ TIM3 CD27 CD7 DAP10TIM3 CD27 CD7 DAP12 TIM3 CD27 CD7 CD32 TIM3 CD27 CD7 CD79a TIM3 CD27 CD7CD79b TIM3 CD27 BTNL3 CD8 TIM3 CD27 BTNL3 CD3ζ TIM3 CD27 BTNL3 CD3δ TIM3CD27 BTNL3 CD3γ TIM3 CD27 BTNL3 CD3ε TIM3 CD27 BTNL3 FcγRI-γ TIM3 CD27BTNL3 FcγRIII-γ TIM3 CD27 BTNL3 FcεRIβ TIM3 CD27 BTNL3 FcεRIγ TIM3 CD27BTNL3 DAP10 TIM3 CD27 BTNL3 DAP12 TIM3 CD27 BTNL3 CD32 TIM3 CD27 BTNL3CD79a TIM3 CD27 BTNL3 CD79b TIM3 CD27 NKG2D CD8 TIM3 CD27 NKG2D CD3ζTIM3 CD27 NKG2D CD3δ TIM3 CD27 NKG2D CD3γ TIM3 CD27 NKG2D CD3ε TIM3 CD27NKG2D FcγRI-γ TIM3 CD27 NKG2D FcγRIII-γ TIM3 CD27 NKG2D FcεRIβ TIM3 CD27NKG2D FcεRIγ TIM3 CD27 NKG2D DAP10 TIM3 CD27 NKG2D DAP12 TIM3 CD27 NKG2DCD32 TIM3 CD27 NKG2D CD79a TIM3 CD27 NKG2D CD79b TIM3 CD28δ CD28 CD8TIM3 CD28δ CD28 CD3ζ TIM3 CD28δ CD28 CD3δ TIM3 CD28δ CD28 CD3γ TIM3CD28δ CD28 CD3ε TIM3 CD28δ CD28 FcγRI-γ TIM3 CD28δ CD28 FcγRIII-γ TIM3CD28δ CD28 FcεRIβ TIM3 CD28δ CD28 FcεRIγ TIM3 CD28δ CD28 DAP10 TIM3CD28δ CD28 DAP12 TIM3 CD28δ CD28 CD32 TIM3 CD28δ CD28 CD79a TIM3 CD28δCD28 CD79b TIM3 CD28δ CD8 CD8 TIM3 CD28δ CD8 CD3ζ TIM3 CD28δ CD8 CD3δTIM3 CD28δ CD8 CD3γ TIM3 CD28δ CD8 CD3ε TIM3 CD28δ CD8 FcγRI-γ TIM3CD28δ CD8 FcγRIII-γ TIM3 CD28δ CD8 FcεRIβ TIM3 CD28δ CD8 FcεRIγ TIM3CD28δ CD8 DAP10 TIM3 CD28δ CD8 DAP12 TIM3 CD28δ CD8 CD32 TIM3 CD28δ CD8CD79a TIM3 CD28δ CD8 CD79b TIM3 CD28δ CD4 CD8 TIM3 CD28δ CD4 CD3ζ TIM3CD28δ CD4 CD3δ TIM3 CD28δ CD4 CD3γ TIM3 CD28δ CD4 CD3ε TIM3 CD28δ CD4FcγRI-γ TIM3 CD28δ CD4 FcγRIII-γ TIM3 CD28δ CD4 FcεRIβ TIM3 CD28δ CD4FcεRIγ TIM3 CD28δ CD4 DAP10 TIM3 CD28δ CD4 DAP12 TIM3 CD28δ CD4 CD32TIM3 CD28δ CD4 CD79a TIM3 CD28δ CD4 CD79b TIM3 CD28δ b2c CD8 TIM3 CD28δb2c CD3ζ TIM3 CD28δ b2c CD3δ TIM3 CD28δ b2c CD3γ TIM3 CD28δ b2c CD3εTIM3 CD28δ b2c FcγRI-γ TIM3 CD28δ b2c FcγRIII-γ TIM3 CD28δ b2c FcεRIβTIM3 CD28δ b2c FcεRIγ TIM3 CD28δ b2c DAP10 TIM3 CD28δ b2c DAP12 TIM3CD28δ b2c CD32 TIM3 CD28δ b2c CD79a TIM3 CD28δ b2c CD79b TIM3 CD28δCD137/41BB CD8 TIM3 CD28δ CD137/41BB CD3ζ TIM3 CD28δ CD137/41BB CD3δTIM3 CD28δ CD137/41BB CD3γ TIM3 CD28δ CD137/41BB CD3ε TIM3 CD28δCD137/41BB FcγRI-γ TIM3 CD28δ CD137/41BB FcγRIII-γ TIM3 CD28δ CD137/41BBFcεRIβ TIM3 CD28δ CD137/41BB FcεRIγ TIM3 CD28δ CD137/41BB DAP10 TIM3CD28δ CD137/41BB DAP12 TIM3 CD28δ CD137/41BB CD32 TIM3 CD28δ CD137/41BBCD79a TIM3 CD28δ CD137/41BB CD79b TIM3 CD28δ ICOS CD8 TIM3 CD28δ ICOSCD3ζ TIM3 CD28δ ICOS CD3δ TIM3 CD28δ ICOS CD3γ TIM3 CD28δ ICOS CD3ε TIM3CD28δ ICOS FcγRI-γ TIM3 CD28δ ICOS FcγRIII-γ TIM3 CD28δ ICOS FcεRIβ TIM3CD28δ ICOS FcεRIγ TIM3 CD28δ ICOS DAP10 TIM3 CD28δ ICOS DAP12 TIM3 CD28δICOS CD32 TIM3 CD28δ ICOS CD79a TIM3 CD28δ ICOS CD79b TIM3 CD28δ CD27CD8 TIM3 CD28δ CD27 CD3ζ TIM3 CD28δ CD27 CD3δ TIM3 CD28δ CD27 CD3γ TIM3CD28δ CD27 CD3ε TIM3 CD28δ CD27 FcγRI-γ TIM3 CD28δ CD27 FcγRIII-γ TIM3CD28δ CD27 FcεRIβ TIM3 CD28δ CD27 FcεRIγ TIM3 CD28δ CD27 DAP10 TIM3CD28δ CD27 DAP12 TIM3 CD28δ CD27 CD32 TIM3 CD28δ CD27 CD79a TIM3 CD28δCD27 CD79b TIM3 CD28δ CD28δ CD8 TIM3 CD28δ CD28δ CD3ζ TIM3 CD28δ CD28δCD3δ TIM3 CD28δ CD28δ CD3γ TIM3 CD28δ CD28δ CD3ε TIM3 CD28δ CD28δFcγRI-γ TIM3 CD28δ CD28δ FcγRIII-γ TIM3 CD28δ CD28δ FcεRIβ TIM3 CD28δCD28δ FcεRIγ TIM3 CD28δ CD28δ DAP10 TIM3 CD28δ CD28δ DAP12 TIM3 CD28δCD28δ CD32 TIM3 CD28δ CD28δ CD79a TIM3 CD28δ CD28δ CD79b TIM3 CD28δ CD80CD8 TIM3 CD28δ CD80 CD3ζ TIM3 CD28δ CD80 CD3δ TIM3 CD28δ CD80 CD3γ TIM3CD28δ CD80 CD3ε TIM3 CD28δ CD80 FcγRI-γ TIM3 CD28δ CD80 FcγRIII-γ TIM3CD28δ CD80 FcεRIβ TIM3 CD28δ CD80 FcεRIγ TIM3 CD28δ CD80 DAP10 TIM3CD28δ CD80 DAP12 TIM3 CD28δ CD80 CD32 TIM3 CD28δ CD80 CD79a TIM3 CD28δCD80 CD79b TIM3 CD28δ CD86 CD8 TIM3 CD28δ CD86 CD3ζ TIM3 CD28δ CD86 CD3δTIM3 CD28δ CD86 CD3γ TIM3 CD28δ CD86 CD3ε TIM3 CD28δ CD86 FcγRI-γ TIM3CD28δ CD86 FcγRIII-γ TIM3 CD28δ CD86 FcεRIβ TIM3 CD28δ CD86 FcεRIγ TIM3CD28δ CD86 DAP10 TIM3 CD28δ CD86 DAP12 TIM3 CD28δ CD86 CD32 TIM3 CD28δCD86 CD79a TIM3 CD28δ CD86 CD79b TIM3 CD28δ OX40 CD8 TIM3 CD28δ OX40CD3ζ TIM3 CD28δ OX40 CD3δ TIM3 CD28δ OX40 CD3γ TIM3 CD28δ OX40 CD3ε TIM3CD28δ OX40 FcγRI-γ TIM3 CD28δ OX40 FcγRIII-γ TIM3 CD28δ OX40 FcεRIβ TIM3CD28δ OX40 FcεRIγ TIM3 CD28δ OX40 DAP10 TIM3 CD28δ OX40 DAP12 TIM3 CD28δOX40 CD32 TIM3 CD28δ OX40 CD79a TIM3 CD28δ OX40 CD79b TIM3 CD28δ DAP10CD8 TIM3 CD28δ DAP10 CD3ζ TIM3 CD28δ DAP10 CD3δ TIM3 CD28δ DAP10 CD3γTIM3 CD28δ DAP10 CD3ε TIM3 CD28δ DAP10 FcγRI-γ TIM3 CD28δ DAP10FcγRIII-γ TIM3 CD28δ DAP10 FcεRIβ TIM3 CD28δ DAP10 FcεRIγ TIM3 CD28δDAP10 DAP10 TIM3 CD28δ DAP10 DAP12 TIM3 CD28δ DAP10 CD32 TIM3 CD28δDAP10 CD79a TIM3 CD28δ DAP10 CD79b TIM3 CD28δ DAP12 CD8 TIM3 CD28δ DAP12CD3ζ TIM3 CD28δ DAP12 CD3δ TIM3 CD28δ DAP12 CD3γ TIM3 CD28δ DAP12 CD3εTIM3 CD28δ DAP12 FcγRI-γ TIM3 CD28δ DAP12 FcγRIII-γ TIM3 CD28δ DAP12FcεRIβ TIM3 CD28δ DAP12 FcεRIγ TIM3 CD28δ DAP12 DAP10 TIM3 CD28δ DAP12DAP12 TIM3 CD28δ DAP12 CD32 TIM3 CD28δ DAP12 CD79a TIM3 CD28δ DAP12CD79b TIM3 CD28δ MyD88 CD8 TIM3 CD28δ MyD88 CD3ζ TIM3 CD28δ MyD88 CD3δTIM3 CD28δ MyD88 CD3γ TIM3 CD28δ MyD88 CD3ε TIM3 CD28δ MyD88 FcγRI-γTIM3 CD28δ MyD88 FcγRIII-γ TIM3 CD28δ MyD88 FcεRIβ TIM3 CD28δ MyD88FcεRIγ TIM3 CD28δ MyD88 DAP10 TIM3 CD28δ MyD88 DAP12 TIM3 CD28δ MyD88CD32 TIM3 CD28δ MyD88 CD79a TIM3 CD28δ MyD88 CD79b TIM3 CD28δ CD7 CD8TIM3 CD28δ CD7 CD3ζ TIM3 CD28δ CD7 CD3δ TIM3 CD28δ CD7 CD3γ TIM3 CD28δCD7 CD3ε TIM3 CD28δ CD7 FcγRI-γ TIM3 CD28δ CD7 FcγRIII-γ TIM3 CD28δ CD7FcεRIβ TIM3 CD28δ CD7 FcεRIγ TIM3 CD28δ CD7 DAP10 TIM3 CD28δ CD7 DAP12TIM3 CD28δ CD7 CD32 TIM3 CD28δ CD7 CD79a TIM3 CD28δ CD7 CD79b TIM3 CD28δBTNL3 CD8 TIM3 CD28δ BTNL3 CD3ζ TIM3 CD28δ BTNL3 CD3δ TIM3 CD28δ BTNL3CD3γ TIM3 CD28δ BTNL3 CD3ε TIM3 CD28δ BTNL3 FcγRI-γ TIM3 CD28δ BTNL3FcγRIII-γ TIM3 CD28δ BTNL3 FcεRIβ TIM3 CD28δ BTNL3 FcεRIγ TIM3 CD28δBTNL3 DAP10 TIM3 CD28δ BTNL3 DAP12 TIM3 CD28δ BTNL3 CD32 TIM3 CD28δBTNL3 CD79a TIM3 CD28δ BTNL3 CD79b TIM3 CD28δ NKG2D CD8 TIM3 CD28δ NKG2DCD3ζ TIM3 CD28δ NKG2D CD3δ TIM3 CD28δ NKG2D CD3γ TIM3 CD28δ NKG2D CD3εTIM3 CD28δ NKG2D FcγRI-γ TIM3 CD28δ NKG2D FcγRIII-γ TIM3 CD28δ NKG2DFcεRIβ TIM3 CD28δ NKG2D FcεRIγ TIM3 CD28δ NKG2D DAP10 TIM3 CD28δ NKG2DDAP12 TIM3 CD28δ NKG2D CD32 TIM3 CD28δ NKG2D CD79a TIM3 CD28δ NKG2DCD79b TIM3 CD80 CD28 CD8 TIM3 CD80 CD28 CD3ζ TIM3 CD80 CD28 CD3δ TIM3CD80 CD28 CD3γ TIM3 CD80 CD28 CD3ε TIM3 CD80 CD28 FcγRI-γ TIM3 CD80 CD28FcγRIII-γ TIM3 CD80 CD28 FcεRIβ TIM3 CD80 CD28 FcεRIγ TIM3 CD80 CD28DAP10 TIM3 CD80 CD28 DAP12 TIM3 CD80 CD28 CD32 TIM3 CD80 CD28 CD79a TIM3CD80 CD28 CD79b TIM3 CD80 CD8 CD8 TIM3 CD80 CD8 CD3ζ TIM3 CD80 CD8 CD3δTIM3 CD80 CD8 CD3γ TIM3 CD80 CD8 CD3ε TIM3 CD80 CD8 FcγRI-γ TIM3 CD80CD8 FcγRIII-γ TIM3 CD80 CD8 FcεRIβ TIM3 CD80 CD8 FcεRIγ TIM3 CD80 CD8DAP10 TIM3 CD80 CD8 DAP12 TIM3 CD80 CD8 CD32 TIM3 CD80 CD8 CD79a TIM3CD80 CD8 CD79b TIM3 CD80 CD4 CD8 TIM3 CD80 CD4 CD3ζ TIM3 CD80 CD4 CD3δTIM3 CD80 CD4 CD3γ TIM3 CD80 CD4 CD3ε TIM3 CD80 CD4 FcγRI-γ TIM3 CD80CD4 FcγRIII-γ TIM3 CD80 CD4 FcεRIβ TIM3 CD80 CD4 FcεRIγ TIM3 CD80 CD4DAP10 TIM3 CD80 CD4 DAP12 TIM3 CD80 CD4 CD32 TIM3 CD80 CD4 CD79a TIM3CD80 CD4 CD79b TIM3 CD80 b2c CD8 TIM3 CD80 b2c CD3ζ TIM3 CD80 b2c CD3δTIM3 CD80 b2c CD3γ TIM3 CD80 b2c CD3ε TIM3 CD80 b2c FcγRI-γ TIM3 CD80b2c FcγRIII-γ TIM3 CD80 b2c FcεRIβ TIM3 CD80 b2c FcεRIγ TIM3 CD80 b2cDAP10 TIM3 CD80 b2c DAP12 TIM3 CD80 b2c CD32 TIM3 CD80 b2c CD79a TIM3CD80 b2c CD79b TIM3 CD80 CD137/41BB CD8 TIM3 CD80 CD137/41BB CD3ζ TIM3CD80 CD137/41BB CD3δ TIM3 CD80 CD137/41BB CD3γ TIM3 CD80 CD137/41BB CD3εTIM3 CD80 CD137/41BB FcγRI-γ TIM3 CD80 CD137/41BB FcγRIII-γ TIM3 CD80CD137/41BB FcεRIβ TIM3 CD80 CD137/41BB FcεRIγ TIM3 CD80 CD137/41BB DAP10TIM3 CD80 CD137/41BB DAP12 TIM3 CD80 CD137/41BB CD32 TIM3 CD80CD137/41BB CD79a TIM3 CD80 CD137/41BB CD79b TIM3 CD80 ICOS CD8 TIM3 CD80ICOS CD3ζ TIM3 CD80 ICOS CD3δ TIM3 CD80 ICOS CD3γ TIM3 CD80 ICOS CD3εTIM3 CD80 ICOS FcγRI-γ TIM3 CD80 ICOS FcγRIII-γ TIM3 CD80 ICOS FcεRIβTIM3 CD80 ICOS FcεRIγ TIM3 CD80 ICOS DAP10 TIM3 CD80 ICOS DAP12 TIM3CD80 ICOS CD32 TIM3 CD80 ICOS CD79a TIM3 CD80 ICOS CD79b TIM3 CD80 CD27CD8 TIM3 CD80 CD27 CD3ζ TIM3 CD80 CD27 CD3δ TIM3 CD80 CD27 CD3γ TIM3CD80 CD27 CD3ε TIM3 CD80 CD27 FcγRI-γ TIM3 CD80 CD27 FcγRIII-γ TIM3 CD80CD27 FcεRIβ TIM3 CD80 CD27 FcεRIγ TIM3 CD80 CD27 DAP10 TIM3 CD80 CD27DAP12 TIM3 CD80 CD27 CD32 TIM3 CD80 CD27 CD79a TIM3 CD80 CD27 CD79b TIM3CD80 CD28δ CD8 TIM3 CD80 CD28δ CD3ζ TIM3 CD80 CD28δ CD3δ TIM3 CD80 CD28δCD3γ TIM3 CD80 CD28δ CD3ε TIM3 CD80 CD28δ FcγRI-γ TIM3 CD80 CD28δFcγRIII-γ TIM3 CD80 CD28δ FcεRIβ TIM3 CD80 CD28δ FcεRIγ TIM3 CD80 CD28δDAP10 TIM3 CD80 CD28δ DAP12 TIM3 CD80 CD28δ CD32 TIM3 CD80 CD28δ CD79aTIM3 CD80 CD28δ CD79b TIM3 CD80 CD80 CD8 TIM3 CD80 CD80 CD3ζ TIM3 CD80CD80 CD3δ TIM3 CD80 CD80 CD3γ TIM3 CD80 CD80 CD3ε TIM3 CD80 CD80 FcγRI-γTIM3 CD80 CD80 FcγRIII-γ TIM3 CD80 CD80 FcεRIβ TIM3 CD80 CD80 FcεRIγTIM3 CD80 CD80 DAP10 TIM3 CD80 CD80 DAP12 TIM3 CD80 CD80 CD32 TIM3 CD80CD80 CD79a TIM3 CD80 CD80 CD79b TIM3 CD80 CD86 CD8 TIM3 CD80 CD86 CD3ζTIM3 CD80 CD86 CD3δ TIM3 CD80 CD86 CD3γ TIM3 CD80 CD86 CD3ε TIM3 CD80CD86 FcγRI-γ TIM3 CD80 CD86 FcγRIII-γ TIM3 CD80 CD86 FcεRIβ TIM3 CD80CD86 FcεRIγ TIM3 CD80 CD86 DAP10 TIM3 CD80 CD86 DAP12 TIM3 CD80 CD86CD32 TIM3 CD80 CD86 CD79a TIM3 CD80 CD86 CD79b TIM3 CD80 OX40 CD8 TIM3CD80 OX40 CD3ζ TIM3 CD80 OX40 CD3δ TIM3 CD80 OX40 CD3γ TIM3 CD80 OX40CD3ε TIM3 CD80 OX40 FcγRI-γ TIM3 CD80 OX40 FcγRIII-γ TIM3 CD80 OX40FcεRIβ TIM3 CD80 OX40 FcεRIγ TIM3 CD80 OX40 DAP10 TIM3 CD80 OX40 DAP12TIM3 CD80 OX40 CD32 TIM3 CD80 OX40 CD79a TIM3 CD80 OX40 CD79b TIM3 CD80DAP10 CD8 TIM3 CD80 DAP10 CD3ζ TIM3 CD80 DAP10 CD3δ TIM3 CD80 DAP10 CD3γTIM3 CD80 DAP10 CD3ε TIM3 CD80 DAP10 FcγRI-γ TIM3 CD80 DAP10 FcγRIII-γTIM3 CD80 DAP10 FcεRIβ TIM3 CD80 DAP10 FcεRIγ TIM3 CD80 DAP10 DAP10 TIM3CD80 DAP10 DAP12 TIM3 CD80 DAP10 CD32 TIM3 CD80 DAP10 CD79a TIM3 CD80DAP10 CD79b TIM3 CD80 DAP12 CD8 TIM3 CD80 DAP12 CD3ζ TIM3 CD80 DAP12CD3δ TIM3 CD80 DAP12 CD3γ TIM3 CD80 DAP12 CD3ε TIM3 CD80 DAP12 FcγRI-γTIM3 CD80 DAP12 FcγRIII-γ TIM3 CD80 DAP12 FcεRIβ TIM3 CD80 DAP12 FcεRIγTIM3 CD80 DAP12 DAP10 TIM3 CD80 DAP12 DAP12 TIM3 CD80 DAP12 CD32 TIM3CD80 DAP12 CD79a TIM3 CD80 DAP12 CD79b TIM3 CD80 MyD88 CD8 TIM3 CD80MyD88 CD3ζ TIM3 CD80 MyD88 CD3δ TIM3 CD80 MyD88 CD3γ TIM3 CD80 MyD88CD3ε TIM3 CD80 MyD88 FcγRI-γ TIM3 CD80 MyD88 FcγRIII-γ TIM3 CD80 MyD88FcεRIβ TIM3 CD80 MyD88 FcεRIγ TIM3 CD80 MyD88 DAP10 TIM3 CD80 MyD88DAP12 TIM3 CD80 MyD88 CD32 TIM3 CD80 MyD88 CD79a TIM3 CD80 MyD88 CD79bTIM3 CD80 CD7 CD8 TIM3 CD80 CD7 CD3ζ TIM3 CD80 CD7 CD3δ TIM3 CD80 CD7CD3γ TIM3 CD80 CD7 CD3ε TIM3 CD80 CD7 FcγRI-γ TIM3 CD80 CD7 FcγRIII-γTIM3 CD80 CD7 FcεRIβ TIM3 CD80 CD7 FcεRIγ TIM3 CD80 CD7 DAP10 TIM3 CD80CD7 DAP12 TIM3 CD80 CD7 CD32 TIM3 CD80 CD7 CD79a TIM3 CD80 CD7 CD79bTIM3 CD80 BTNL3 CD8 TIM3 CD80 BTNL3 CD3ζ TIM3 CD80 BTNL3 CD3δ TIM3 CD80BTNL3 CD3γ TIM3 CD80 BTNL3 CD3ε TIM3 CD80 BTNL3 FcγRI-γ TIM3 CD80 BTNL3FcγRIII-γ TIM3 CD80 BTNL3 FcεRIβ TIM3 CD80 BTNL3 FcεRIγ TIM3 CD80 BTNL3DAP10 TIM3 CD80 BTNL3 DAP12 TIM3 CD80 BTNL3 CD32 TIM3 CD80 BTNL3 CD79aTIM3 CD80 BTNL3 CD79b TIM3 CD80 NKG2D CD8 TIM3 CD80 NKG2D CD3ζ TIM3 CD80NKG2D CD3δ TIM3 CD80 NKG2D CD3γ TIM3 CD80 NKG2D CD3ε TIM3 CD80 NKG2DFcγRI-γ TIM3 CD80 NKG2D FcγRIII-γ TIM3 CD80 NKG2D FcεRIβ TIM3 CD80 NKG2DFcεRIγ TIM3 CD80 NKG2D DAP10 TIM3 CD80 NKG2D DAP12 TIM3 CD80 NKG2D CD32TIM3 CD80 NKG2D CD79a TIM3 CD80 NKG2D CD79b TIM3 CD86 CD28 CD8 TIM3 CD86CD28 CD3ζ TIM3 CD86 CD28 CD3δ TIM3 CD86 CD28 CD3γ TIM3 CD86 CD28 CD3εTIM3 CD86 CD28 FcγRI-γ TIM3 CD86 CD28 FcγRIII-γ TIM3 CD86 CD28 FcεRIβTIM3 CD86 CD28 FcεRIγ TIM3 CD86 CD28 DAP10 TIM3 CD86 CD28 DAP12 TIM3CD86 CD28 CD32 TIM3 CD86 CD28 CD79a TIM3 CD86 CD28 CD79b TIM3 CD86 CD8CD8 TIM3 CD86 CD8 CD3ζ TIM3 CD86 CD8 CD3δ TIM3 CD86 CD8 CD3γ TIM3 CD86CD8 CD3ε TIM3 CD86 CD8 FcγRI-γ TIM3 CD86 CD8 FcγRIII-γ TIM3 CD86 CD8FcεRIβ TIM3 CD86 CD8 FcεRIγ TIM3 CD86 CD8 DAP10 TIM3 CD86 CD8 DAP12 TIM3CD86 CD8 CD32 TIM3 CD86 CD8 CD79a TIM3 CD86 CD8 CD79b TIM3 CD86 CD4 CD8TIM3 CD86 CD4 CD3ζ TIM3 CD86 CD4 CD3δ TIM3 CD86 CD4 CD3γ TIM3 CD86 CD4CD3ε TIM3 CD86 CD4 FcγRI-γ TIM3 CD86 CD4 FcγRIII-γ TIM3 CD86 CD4 FcεRIβTIM3 CD86 CD4 FcεRIγ TIM3 CD86 CD4 DAP10 TIM3 CD86 CD4 DAP12 TIM3 CD86CD4 CD32 TIM3 CD86 CD4 CD79a TIM3 CD86 CD4 CD79b TIM3 CD86 b2c CD8 TIM3CD86 b2c CD3ζ TIM3 CD86 b2c CD3δ TIM3 CD86 b2c CD3γ TIM3 CD86 b2c CD3εTIM3 CD86 b2c FcγRI-γ TIM3 CD86 b2c FcγRIII-γ TIM3 CD86 b2c FcεRIβ TIM3CD86 b2c FcεRIγ TIM3 CD86 b2c DAP10 TIM3 CD86 b2c DAP12 TIM3 CD86 b2cCD32 TIM3 CD86 b2c CD79a TIM3 CD86 b2c CD79b TIM3 CD86 CD137/41BB CD8TIM3 CD86 CD137/41BB CD3ζ TIM3 CD86 CD137/41BB CD3δ TIM3 CD86 CD137/41BBCD3γ TIM3 CD86 CD137/41BB CD3ε TIM3 CD86 CD137/41BB FcγRI-γ TIM3 CD86CD137/41BB FcγRIII-γ TIM3 CD86 CD137/41BB FcεRIβ TIM3 CD86 CD137/41BBFcεRIγ TIM3 CD86 CD137/41BB DAP10 TIM3 CD86 CD137/41BB DAP12 TIM3 CD86CD137/41BB CD32 TIM3 CD86 CD137/41BB CD79a TIM3 CD86 CD137/41BB CD79bTIM3 CD86 ICOS CD8 TIM3 CD86 ICOS CD3ζ TIM3 CD86 ICOS CD3δ TIM3 CD86ICOS CD3γ TIM3 CD86 ICOS CD3ε TIM3 CD86 ICOS FcγRI-γ TIM3 CD86 ICOSFcγRIII-γ TIM3 CD86 ICOS FcεRIβ TIM3 CD86 ICOS FcεRIγ TIM3 CD86 ICOSDAP10 TIM3 CD86 ICOS DAP12 TIM3 CD86 ICOS CD32 TIM3 CD86 ICOS CD79a TIM3CD86 ICOS CD79b TIM3 CD86 CD27 CD8 TIM3 CD86 CD27 CD3ζ TIM3 CD86 CD27CD3δ TIM3 CD86 CD27 CD3γ TIM3 CD86 CD27 CD3ε TIM3 CD86 CD27 FcγRI-γ TIM3CD86 CD27 FcγRIII-γ TIM3 CD86 CD27 FcεRIβ TIM3 CD86 CD27 FcεRIγ TIM3CD86 CD27 DAP10 TIM3 CD86 CD27 DAP12 TIM3 CD86 CD27 CD32 TIM3 CD86 CD27CD79a TIM3 CD86 CD27 CD79b TIM3 CD86 CD28δ CD8 TIM3 CD86 CD28δ CD3ζ TIM3CD86 CD28δ CD3δ TIM3 CD86 CD28δ CD3γ TIM3 CD86 CD28δ CD3ε TIM3 CD86CD28δ FcγRI-γ TIM3 CD86 CD28δ FcγRIII-γ TIM3 CD86 CD28δ FcεRIβ TIM3 CD86CD28δ FcεRIγ TIM3 CD86 CD28δ DAP10 TIM3 CD86 CD28δ DAP12 TIM3 CD86 CD28δCD32 TIM3 CD86 CD28δ CD79a TIM3 CD86 CD28δ CD79b TIM3 CD86 CD80 CD8 TIM3CD86 CD80 CD3ζ TIM3 CD86 CD80 CD3δ TIM3 CD86 CD80 CD3γ TIM3 CD86 CD80CD3ε TIM3 CD86 CD80 FcγRI-γ TIM3 CD86 CD80 FcγRIII-γ TIM3 CD86 CD80FcεRIβ TIM3 CD86 CD80 FcεRIγ TIM3 CD86 CD80 DAP10 TIM3 CD86 CD80 DAP12TIM3 CD86 CD80 CD32 TIM3 CD86 CD80 CD79a TIM3 CD86 CD80 CD79b TIM3 CD86CD86 CD8 TIM3 CD86 CD86 CD3ζ TIM3 CD86 CD86 CD3δ TIM3 CD86 CD86 CD3γTIM3 CD86 CD86 CD3ε TIM3 CD86 CD86 FcγRI-γ TIM3 CD86 CD86 FcγRIII-γ TIM3CD86 CD86 FcεRIβ TIM3 CD86 CD86 FcεRIγ TIM3 CD86 CD86 DAP10 TIM3 CD86CD86 DAP12 TIM3 CD86 CD86 CD32 TIM3 CD86 CD86 CD79a TIM3 CD86 CD86 CD79bTIM3 CD86 OX40 CD8 TIM3 CD86 OX40 CD3ζ TIM3 CD86 OX40 CD3δ TIM3 CD86OX40 CD3γ TIM3 CD86 OX40 CD3ε TIM3 CD86 OX40 FcγRI-γ TIM3 CD86 OX40FcγRIII-γ TIM3 CD86 OX40 FcεRIβ TIM3 CD86 OX40 FcεRIγ TIM3 CD86 OX40DAP10 TIM3 CD86 OX40 DAP12 TIM3 CD86 OX40 CD32 TIM3 CD86 OX40 CD79a TIM3CD86 OX40 CD79b TIM3 CD86 DAP10 CD8 TIM3 CD86 DAP10 CD3ζ TIM3 CD86 DAP10CD3δ TIM3 CD86 DAP10 CD3γ TIM3 CD86 DAP10 CD3ε TIM3 CD86 DAP10 FcγRI-γTIM3 CD86 DAP10 FcγRIII-γ TIM3 CD86 DAP10 FcεRIβ TIM3 CD86 DAP10 FcεRIγTIM3 CD86 DAP10 DAP10 TIM3 CD86 DAP10 DAP12 TIM3 CD86 DAP10 CD32 TIM3CD86 DAP10 CD79a TIM3 CD86 DAP10 CD79b TIM3 CD86 DAP12 CD8 TIM3 CD86DAP12 CD3ζ TIM3 CD86 DAP12 CD3δ TIM3 CD86 DAP12 CD3γ TIM3 CD86 DAP12CD3ε TIM3 CD86 DAP12 FcγRI-γ TIM3 CD86 DAP12 FcγRIII-γ TIM3 CD86 DAP12FcεRIβ TIM3 CD86 DAP12 FcεRIγ TIM3 CD86 DAP12 DAP10 TIM3 CD86 DAP12DAP12 TIM3 CD86 DAP12 CD32 TIM3 CD86 DAP12 CD79a TIM3 CD86 DAP12 CD79bTIM3 CD86 MyD88 CD8 TIM3 CD86 MyD88 CD3ζ TIM3 CD86 MyD88 CD3δ TIM3 CD86MyD88 CD3γ TIM3 CD86 MyD88 CD3ε TIM3 CD86 MyD88 FcγRI-γ TIM3 CD86 MyD88FcγRIII-γ TIM3 CD86 MyD88 FcεRIβ TIM3 CD86 MyD88 FcεRIγ TIM3 CD86 MyD88DAP10 TIM3 CD86 MyD88 DAP12 TIM3 CD86 MyD88 CD32 TIM3 CD86 MyD88 CD79aTIM3 CD86 MyD88 CD79b TIM3 CD86 CD7 CD8 TIM3 CD86 CD7 CD3ζ TIM3 CD86 CD7CD3δ TIM3 CD86 CD7 CD3γ TIM3 CD86 CD7 CD3ε TIM3 CD86 CD7 FcγRI-γ TIM3CD86 CD7 FcγRIII-γ TIM3 CD86 CD7 FcεRIβ TIM3 CD86 CD7 FcεRIγ TIM3 CD86CD7 DAP10 TIM3 CD86 CD7 DAP12 TIM3 CD86 CD7 CD32 TIM3 CD86 CD7 CD79aTIM3 CD86 CD7 CD79b TIM3 CD86 BTNL3 CD8 TIM3 CD86 BTNL3 CD3ζ TIM3 CD86BTNL3 CD3δ TIM3 CD86 BTNL3 CD3γ TIM3 CD86 BTNL3 CD3ε TIM3 CD86 BTNL3FcγRI-γ TIM3 CD86 BTNL3 FcγRIII-γ TIM3 CD86 BTNL3 FcεRIβ TIM3 CD86 BTNL3FcεRIγ TIM3 CD86 BTNL3 DAP10 TIM3 CD86 BTNL3 DAP12 TIM3 CD86 BTNL3 CD32TIM3 CD86 BTNL3 CD79a TIM3 CD86 BTNL3 CD79b TIM3 CD86 NKG2D CD8 TIM3CD86 NKG2D CD3ζ TIM3 CD86 NKG2D CD3δ TIM3 CD86 NKG2D CD3γ TIM3 CD86NKG2D CD3ε TIM3 CD86 NKG2D FcγRI-γ TIM3 CD86 NKG2D FcγRIII-γ TIM3 CD86NKG2D FcεRIβ TIM3 CD86 NKG2D FcεRIγ TIM3 CD86 NKG2D DAP10 TIM3 CD86NKG2D DAP12 TIM3 CD86 NKG2D CD32 TIM3 CD86 NKG2D CD79a TIM3 CD86 NKG2DCD79b TIM3 OX40 CD28 CD8 TIM3 OX40 CD28 CD3ζ TIM3 OX40 CD28 CD3δ TIM3OX40 CD28 CD3γ TIM3 OX40 CD28 CD3ε TIM3 OX40 CD28 FcγRI-γ TIM3 OX40 CD28FcγRIII-γ TIM3 OX40 CD28 FcεRIβ TIM3 OX40 CD28 FcεRIγ TIM3 OX40 CD28DAP10 TIM3 OX40 CD28 DAP12 TIM3 OX40 CD28 CD32 TIM3 OX40 CD28 CD79a TIM3OX40 CD28 CD79b TIM3 OX40 CD8 CD8 TIM3 OX40 CD8 CD3ζ TIM3 OX40 CD8 CD3δTIM3 OX40 CD8 CD3γ TIM3 OX40 CD8 CD3ε TIM3 OX40 CD8 FcγRI-γ TIM3 OX40CD8 FcγRIII-γ TIM3 OX40 CD8 FcεRIβ TIM3 OX40 CD8 FcεRIγ TIM3 OX40 CD8DAP10 TIM3 OX40 CD8 DAP12 TIM3 OX40 CD8 CD32 TIM3 OX40 CD8 CD79a TIM3OX40 CD8 CD79b TIM3 OX40 CD4 CD8 TIM3 OX40 CD4 CD3ζ TIM3 OX40 CD4 CD3δTIM3 OX40 CD4 CD3γ TIM3 OX40 CD4 CD3ε TIM3 OX40 CD4 FcγRI-γ TIM3 OX40CD4 FcγRIII-γ TIM3 OX40 CD4 FcεRIβ TIM3 OX40 CD4 FcεRIγ TIM3 OX40 CD4DAP10 TIM3 OX40 CD4 DAP12 TIM3 OX40 CD4 CD32 TIM3 OX40 CD4 CD79a TIM3OX40 CD4 CD79b TIM3 OX40 b2c CD8 TIM3 OX40 b2c CD3ζ TIM3 OX40 b2c CD3δTIM3 OX40 b2c CD3γ TIM3 OX40 b2c CD3ε TIM3 OX40 b2c FcγRI-γ TIM3 OX40b2c FcγRIII-γ TIM3 OX40 b2c FcεRIβ TIM3 OX40 b2c FcεRIγ TIM3 OX40 b2cDAP10 TIM3 OX40 b2c DAP12 TIM3 OX40 b2c CD32 TIM3 OX40 b2c CD79a TIM3OX40 b2c CD79b TIM3 OX40 CD137/41BB CD8 TIM3 OX40 CD137/41BB CD3ζ TIM3OX40 CD137/41BB CD3δ TIM3 OX40 CD137/41BB CD3γ TIM3 OX40 CD137/41BB CD3εTIM3 OX40 CD137/41BB FcγRI-γ TIM3 OX40 CD137/41BB FcγRIII-γ TIM3 OX40CD137/41BB FcεRIβ TIM3 OX40 CD137/41BB FcεRIγ TIM3 OX40 CD137/41BB DAP10TIM3 OX40 CD137/41BB DAP12 TIM3 OX40 CD137/41BB CD32 TIM3 OX40CD137/41BB CD79a TIM3 OX40 CD137/41BB CD79b TIM3 OX40 ICOS CD8 TIM3 OX40ICOS CD3ζ TIM3 OX40 ICOS CD3δ TIM3 OX40 ICOS CD3γ TIM3 OX40 ICOS CD3εTIM3 OX40 ICOS FcγRI-γ TIM3 OX40 ICOS FcγRIII-γ TIM3 OX40 ICOS FcεRIβTIM3 OX40 ICOS FcεRIγ TIM3 OX40 ICOS DAP10 TIM3 OX40 ICOS DAP12 TIM3OX40 ICOS CD32 TIM3 OX40 ICOS CD79a TIM3 OX40 ICOS CD79b TIM3 OX40 CD27CD8 TIM3 OX40 CD27 CD3ζ TIM3 OX40 CD27 CD3δ TIM3 OX40 CD27 CD3γ TIM3OX40 CD27 CD3ε TIM3 OX40 CD27 FcγRI-γ TIM3 OX40 CD27 FcγRIII-γ TIM3 OX40CD27 FcεRIβ TIM3 OX40 CD27 FcεRIγ TIM3 OX40 CD27 DAP10 TIM3 OX40 CD27DAP12 TIM3 OX40 CD27 CD32 TIM3 OX40 CD27 CD79a TIM3 OX40 CD27 CD79b TIM3OX40 CD28δ CD8 TIM3 OX40 CD28δ CD3ζ TIM3 OX40 CD28δ CD3δ TIM3 OX40 CD28δCD3γ TIM3 OX40 CD28δ CD3ε TIM3 OX40 CD28δ FcγRI-γ TIM3 OX40 CD28δFcγRIII-γ TIM3 OX40 CD28δ FcεRIβ TIM3 OX40 CD28δ FcεRIγ TIM3 OX40 CD28δDAP10 TIM3 OX40 CD28δ DAP12 TIM3 OX40 CD28δ CD32 TIM3 OX40 CD28δ CD79aTIM3 OX40 CD28δ CD79b TIM3 OX40 CD80 CD8 TIM3 OX40 CD80 CD3ζ TIM3 OX40CD80 CD3δ TIM3 OX40 CD80 CD3γ TIM3 OX40 CD80 CD3ε TIM3 OX40 CD80 FcγRI-γTIM3 OX40 CD80 FcγRIII-γ TIM3 OX40 CD80 FcεRIβ TIM3 OX40 CD80 FcεRIγTIM3 OX40 CD80 DAP10 TIM3 OX40 CD80 DAP12 TIM3 OX40 CD80 CD32 TIM3 OX40CD80 CD79a TIM3 OX40 CD80 CD79b TIM3 OX40 CD86 CD8 TIM3 OX40 CD86 CD3ζTIM3 OX40 CD86 CD3δ TIM3 OX40 CD86 CD3γ TIM3 OX40 CD86 CD3ε TIM3 OX40CD86 FcγRI-γ TIM3 OX40 CD86 FcγRIII-γ TIM3 OX40 CD86 FcεRIβ TIM3 OX40CD86 FcεRIγ TIM3 OX40 CD86 DAP10 TIM3 OX40 CD86 DAP12 TIM3 OX40 CD86CD32 TIM3 OX40 CD86 CD79a TIM3 OX40 CD86 CD79b TIM3 OX40 OX40 CD8 TIM3OX40 OX40 CD3ζ TIM3 OX40 OX40 CD3δ TIM3 OX40 OX40 CD3γ TIM3 OX40 OX40CD3ε TIM3 OX40 OX40 FcγRI-γ TIM3 OX40 OX40 FcγRIII-γ TIM3 OX40 OX40FcεRIβ TIM3 OX40 OX40 FcεRIγ TIM3 OX40 OX40 DAP10 TIM3 OX40 OX40 DAP12TIM3 OX40 OX40 CD32 TIM3 OX40 OX40 CD79a TIM3 OX40 OX40 CD79b TIM3 OX40DAP10 CD8 TIM3 OX40 DAP10 CD3ζ TIM3 OX40 DAP10 CD3δ TIM3 OX40 DAP10 CD3γTIM3 OX40 DAP10 CD3ε TIM3 OX40 DAP10 FcγRI-γ TIM3 OX40 DAP10 FcγRIII-γTIM3 OX40 DAP10 FcεRIβ TIM3 OX40 DAP10 FcεRIγ TIM3 OX40 DAP10 DAP10 TIM3OX40 DAP10 DAP12 TIM3 OX40 DAP10 CD32 TIM3 OX40 DAP10 CD79a TIM3 OX40DAP10 CD79b TIM3 OX40 DAP12 CD8 TIM3 OX40 DAP12 CD3ζ TIM3 OX40 DAP12CD3δ TIM3 OX40 DAP12 CD3γ TIM3 OX40 DAP12 CD3ε TIM3 OX40 DAP12 FcγRI-γTIM3 OX40 DAP12 FcγRIII-γ TIM3 OX40 DAP12 FcεRIβ TIM3 OX40 DAP12 FcεRIγTIM3 OX40 DAP12 DAP10 TIM3 OX40 DAP12 DAP12 TIM3 OX40 DAP12 CD32 TIM3OX40 DAP12 CD79a TIM3 OX40 DAP12 CD79b TIM3 OX40 MyD88 CD8 TIM3 OX40MyD88 CD3ζ TIM3 OX40 MyD88 CD3δ TIM3 OX40 MyD88 CD3γ TIM3 OX40 MyD88CD3ε TIM3 OX40 MyD88 FcγRI-γ TIM3 OX40 MyD88 FcγRIII-γ TIM3 OX40 MyD88FcεRIβ TIM3 OX40 MyD88 FcεRIγ TIM3 OX40 MyD88 DAP10 TIM3 OX40 MyD88DAP12 TIM3 OX40 MyD88 CD32 TIM3 OX40 MyD88 CD79a TIM3 OX40 MyD88 CD79bTIM3 OX40 CD7 CD8 TIM3 OX40 CD7 CD3ζ TIM3 OX40 CD7 CD3δ TIM3 OX40 CD7CD3γ TIM3 OX40 CD7 CD3ε TIM3 OX40 CD7 FcγRI-γ TIM3 OX40 CD7 FcγRIII-γTIM3 OX40 CD7 FcεRIβ TIM3 OX40 CD7 FcεRIγ TIM3 OX40 CD7 DAP10 TIM3 OX40CD7 DAP12 TIM3 OX40 CD7 CD32 TIM3 OX40 CD7 CD79a TIM3 OX40 CD7 CD79bTIM3 OX40 BTNL3 CD8 TIM3 OX40 BTNL3 CD3ζ TIM3 OX40 BTNL3 CD3δ TIM3 OX40BTNL3 CD3γ TIM3 OX40 BTNL3 CD3ε TIM3 OX40 BTNL3 FcγRI-γ TIM3 OX40 BTNL3FcγRIII-γ TIM3 OX40 BTNL3 FcεRIβ TIM3 OX40 BTNL3 FcεRIγ TIM3 OX40 BTNL3DAP10 TIM3 OX40 BTNL3 DAP12 TIM3 OX40 BTNL3 CD32 TIM3 OX40 BTNL3 CD79aTIM3 OX40 BTNL3 CD79b TIM3 OX40 NKG2D CD8 TIM3 OX40 NKG2D CD3ζ TIM3 OX40NKG2D CD3δ TIM3 OX40 NKG2D CD3γ TIM3 OX40 NKG2D CD3ε TIM3 OX40 NKG2DFcγRI-γ TIM3 OX40 NKG2D FcγRIII-γ TIM3 OX40 NKG2D FcεRIβ TIM3 OX40 NKG2DFcεRIγ TIM3 OX40 NKG2D DAP10 TIM3 OX40 NKG2D DAP12 TIM3 OX40 NKG2D CD32TIM3 OX40 NKG2D CD79a TIM3 OX40 NKG2D CD79b TIM3 DAP10 CD28 CD8 TIM3DAP10 CD28 CD3ζ TIM3 DAP10 CD28 CD3δ TIM3 DAP10 CD28 CD3γ TIM3 DAP10CD28 CD3ε TIM3 DAP10 CD28 FcγRI-γ TIM3 DAP10 CD28 FcγRIII-γ TIM3 DAP10CD28 FcεRIβ TIM3 DAP10 CD28 FcεRIγ TIM3 DAP10 CD28 DAP10 TIM3 DAP10 CD28DAP12 TIM3 DAP10 CD28 CD32 TIM3 DAP10 CD28 CD79a TIM3 DAP10 CD28 CD79bTIM3 DAP10 CD8 CD8 TIM3 DAP10 CD8 CD3ζ TIM3 DAP10 CD8 CD3δ TIM3 DAP10CD8 CD3γ TIM3 DAP10 CD8 CD3ε TIM3 DAP10 CD8 FcγRI-γ TIM3 DAP10 CD8FcγRIII-γ TIM3 DAP10 CD8 FcεRIβ TIM3 DAP10 CD8 FcεRIγ TIM3 DAP10 CD8DAP10 TIM3 DAP10 CD8 DAP12 TIM3 DAP10 CD8 CD32 TIM3 DAP10 CD8 CD79a TIM3DAP10 CD8 CD79b TIM3 DAP10 CD4 CD8 TIM3 DAP10 CD4 CD3ζ TIM3 DAP10 CD4CD3δ TIM3 DAP10 CD4 CD3γ TIM3 DAP10 CD4 CD3ε TIM3 DAP10 CD4 FcγRI-γ TIM3DAP10 CD4 FcγRIII-γ TIM3 DAP10 CD4 FcεRIβ TIM3 DAP10 CD4 FcεRIγ TIM3DAP10 CD4 DAP10 TIM3 DAP10 CD4 DAP12 TIM3 DAP10 CD4 CD32 TIM3 DAP10 CD4CD79a TIM3 DAP10 CD4 CD79b TIM3 DAP10 b2c CD8 TIM3 DAP10 b2c CD3ζ TIM3DAP10 b2c CD3δ TIM3 DAP10 b2c CD3γ TIM3 DAP10 b2c CD3ε TIM3 DAP10 b2cFcγRI-γ TIM3 DAP10 b2c FcγRIII-γ TIM3 DAP10 b2c FcεRIβ TIM3 DAP10 b2cFcεRIγ TIM3 DAP10 b2c DAP10 TIM3 DAP10 b2c DAP12 TIM3 DAP10 b2c CD32TIM3 DAP10 b2c CD79a TIM3 DAP10 b2c CD79b TIM3 DAP10 CD137/41BB CD8 TIM3DAP10 CD137/41BB CD3ζ TIM3 DAP10 CD137/41BB CD3δ TIM3 DAP10 CD137/41BBCD3γ TIM3 DAP10 CD137/41BB CD3ε TIM3 DAP10 CD137/41BB FcγRI-γ TIM3 DAP10CD137/41BB FcγRIII-γ TIM3 DAP10 CD137/41BB FcεRIβ TIM3 DAP10 CD137/41BBFcεRIγ TIM3 DAP10 CD137/41BB DAP10 TIM3 DAP10 CD137/41BB DAP12 TIM3DAP10 CD137/41BB CD32 TIM3 DAP10 CD137/41BB CD79a TIM3 DAP10 CD137/41BBCD79b TIM3 DAP10 ICOS CD8 TIM3 DAP10 ICOS CD3ζ TIM3 DAP10 ICOS CD3δ TIM3DAP10 ICOS CD3γ TIM3 DAP10 ICOS CD3ε TIM3 DAP10 ICOS FcγRI-γ TIM3 DAP10ICOS FcγRIII-γ TIM3 DAP10 ICOS FcεRIβ TIM3 DAP10 ICOS FcεRIγ TIM3 DAP10ICOS DAP10 TIM3 DAP10 ICOS DAP12 TIM3 DAP10 ICOS CD32 TIM3 DAP10 ICOSCD79a TIM3 DAP10 ICOS CD79b TIM3 DAP10 CD27 CD8 TIM3 DAP10 CD27 CD3ζTIM3 DAP10 CD27 CD3δ TIM3 DAP10 CD27 CD3γ TIM3 DAP10 CD27 CD3ε TIM3DAP10 CD27 FcγRI-γ TIM3 DAP10 CD27 FcγRIII-γ TIM3 DAP10 CD27 FcεRIβ TIM3DAP10 CD27 FcεRIγ TIM3 DAP10 CD27 DAP10 TIM3 DAP10 CD27 DAP12 TIM3 DAP10CD27 CD32 TIM3 DAP10 CD27 CD79a TIM3 DAP10 CD27 CD79b TIM3 DAP10 CD28δCD8 TIM3 DAP10 CD28δ CD3ζ TIM3 DAP10 CD28δ CD3δ TIM3 DAP10 CD28δ CD3γTIM3 DAP10 CD28δ CD3ε TIM3 DAP10 CD28δ FcγRI-γ TIM3 DAP10 CD28δFcγRIII-γ TIM3 DAP10 CD28δ FcεRIβ TIM3 DAP10 CD28δ FcεRIγ TIM3 DAP10CD28δ DAP10 TIM3 DAP10 CD28δ DAP12 TIM3 DAP10 CD28δ CD32 TIM3 DAP10CD28δ CD79a TIM3 DAP10 CD28δ CD79b TIM3 DAP10 CD80 CD8 TIM3 DAP10 CD80CD3ζ TIM3 DAP10 CD80 CD3δ TIM3 DAP10 CD80 CD3γ TIM3 DAP10 CD80 CD3ε TIM3DAP10 CD80 FcγRI-γ TIM3 DAP10 CD80 FcγRIII-γ TIM3 DAP10 CD80 FcεRIβ TIM3DAP10 CD80 FcεRIγ TIM3 DAP10 CD80 DAP10 TIM3 DAP10 CD80 DAP12 TIM3 DAP10CD80 CD32 TIM3 DAP10 CD80 CD79a TIM3 DAP10 CD80 CD79b TIM3 DAP10 CD86CD8 TIM3 DAP10 CD86 CD3ζ TIM3 DAP10 CD86 CD3δ TIM3 DAP10 CD86 CD3γ TIM3DAP10 CD86 CD3ε TIM3 DAP10 CD86 FcγRI-γ TIM3 DAP10 CD86 FcγRIII-γ TIM3DAP10 CD86 FcεRIβ TIM3 DAP10 CD86 FcεRIγ TIM3 DAP10 CD86 DAP10 TIM3DAP10 CD86 DAP12 TIM3 DAP10 CD86 CD32 TIM3 DAP10 CD86 CD79a TIM3 DAP10CD86 CD79b TIM3 DAP10 OX40 CD8 TIM3 DAP10 OX40 CD3ζ TIM3 DAP10 OX40 CD3δTIM3 DAP10 OX40 CD3γ TIM3 DAP10 OX40 CD3ε TIM3 DAP10 OX40 FcγRI-γ TIM3DAP10 OX40 FcγRIII-γ TIM3 DAP10 OX40 FcεRIβ TIM3 DAP10 OX40 FcεRIγ TIM3DAP10 OX40 DAP10 TIM3 DAP10 OX40 DAP12 TIM3 DAP10 OX40 CD32 TIM3 DAP10OX40 CD79a TIM3 DAP10 OX40 CD79b TIM3 DAP10 DAP10 CD8 TIM3 DAP10 DAP10CD3ζ TIM3 DAP10 DAP10 CD3δ TIM3 DAP10 DAP10 CD3γ TIM3 DAP10 DAP10 CD3εTIM3 DAP10 DAP10 FcγRI-γ TIM3 DAP10 DAP10 FcγRIII-γ TIM3 DAP10 DAP10FcεRIβ TIM3 DAP10 DAP10 FcεRIγ TIM3 DAP10 DAP10 DAP10 TIM3 DAP10 DAP10DAP12 TIM3 DAP10 DAP10 CD32 TIM3 DAP10 DAP10 CD79a TIM3 DAP10 DAP10CD79b TIM3 DAP10 DAP12 CD8 TIM3 DAP10 DAP12 CD3ζ TIM3 DAP10 DAP12 CD3δTIM3 DAP10 DAP12 CD3γ TIM3 DAP10 DAP12 CD3ε TIM3 DAP10 DAP12 FcγRI-γTIM3 DAP10 DAP12 FcγRIII-γ TIM3 DAP10 DAP12 FcεRIβ TIM3 DAP10 DAP12FcεRIγ TIM3 DAP10 DAP12 DAP10 TIM3 DAP10 DAP12 DAP12 TIM3 DAP10 DAP12CD32 TIM3 DAP10 DAP12 CD79a TIM3 DAP10 DAP12 CD79b TIM3 DAP10 MyD88 CD8TIM3 DAP10 MyD88 CD3ζ TIM3 DAP10 MyD88 CD3δ TIM3 DAP10 MyD88 CD3γ TIM3DAP10 MyD88 CD3ε TIM3 DAP10 MyD88 FcγRI-γ TIM3 DAP10 MyD88 FcγRIII-γTIM3 DAP10 MyD88 FcεRIβ TIM3 DAP10 MyD88 FcεRIγ TIM3 DAP10 MyD88 DAP10TIM3 DAP10 MyD88 DAP12 TIM3 DAP10 MyD88 CD32 TIM3 DAP10 MyD88 CD79a TIM3DAP10 MyD88 CD79b TIM3 DAP10 CD7 CD8 TIM3 DAP10 CD7 CD3ζ TIM3 DAP10 CD7CD3δ TIM3 DAP10 CD7 CD3γ TIM3 DAP10 CD7 CD3ε TIM3 DAP10 CD7 FcγRI-γ TIM3DAP10 CD7 FcγRIII-γ TIM3 DAP10 CD7 FcεRIβ TIM3 DAP10 CD7 FcεRIγ TIM3DAP10 CD7 DAP10 TIM3 DAP10 CD7 DAP12 TIM3 DAP10 CD7 CD32 TIM3 DAP10 CD7CD79a TIM3 DAP10 CD7 CD79b TIM3 DAP10 BTNL3 CD8 TIM3 DAP10 BTNL3 CD3ζTIM3 DAP10 BTNL3 CD3δ TIM3 DAP10 BTNL3 CD3γ TIM3 DAP10 BTNL3 CD3ε TIM3DAP10 BTNL3 FcγRI-γ TIM3 DAP10 BTNL3 FcγRIII-γ TIM3 DAP10 BTNL3 FcεRIβTIM3 DAP10 BTNL3 FcεRIγ TIM3 DAP10 BTNL3 DAP10 TIM3 DAP10 BTNL3 DAP12TIM3 DAP10 BTNL3 CD32 TIM3 DAP10 BTNL3 CD79a TIM3 DAP10 BTNL3 CD79b TIM3DAP10 NKG2D CD8 TIM3 DAP10 NKG2D CD3ζ TIM3 DAP10 NKG2D CD3δ TIM3 DAP10NKG2D CD3γ TIM3 DAP10 NKG2D CD3ε TIM3 DAP10 NKG2D FcγRI-γ TIM3 DAP10NKG2D FcγRIII-γ TIM3 DAP10 NKG2D FcεRIβ TIM3 DAP10 NKG2D FcεRIγ TIM3DAP10 NKG2D DAP10 TIM3 DAP10 NKG2D DAP12 TIM3 DAP10 NKG2D CD32 TIM3DAP10 NKG2D CD79a TIM3 DAP10 NKG2D CD79b TIM3 DAP12 CD28 CD8 TIM3 DAP12CD28 CD3ζ TIM3 DAP12 CD28 CD3δ TIM3 DAP12 CD28 CD3γ TIM3 DAP12 CD28 CD3εTIM3 DAP12 CD28 FcγRI-γ TIM3 DAP12 CD28 FcγRIII-γ TIM3 DAP12 CD28 FcεRIβTIM3 DAP12 CD28 FcεRIγ TIM3 DAP12 CD28 DAP10 TIM3 DAP12 CD28 DAP12 TIM3DAP12 CD28 CD32 TIM3 DAP12 CD28 CD79a TIM3 DAP12 CD28 CD79b TIM3 DAP12CD8 CD8 TIM3 DAP12 CD8 CD3ζ TIM3 DAP12 CD8 CD3δ TIM3 DAP12 CD8 CD3γ TIM3DAP12 CD8 CD3ε TIM3 DAP12 CD8 FcγRI-γ TIM3 DAP12 CD8 FcγRIII-γ TIM3DAP12 CD8 FcεRIβ TIM3 DAP12 CD8 FcεRIγ TIM3 DAP12 CD8 DAP10 TIM3 DAP12CD8 DAP12 TIM3 DAP12 CD8 CD32 TIM3 DAP12 CD8 CD79a TIM3 DAP12 CD8 CD79bTIM3 DAP12 CD4 CD8 TIM3 DAP12 CD4 CD3ζ TIM3 DAP12 CD4 CD3δ TIM3 DAP12CD4 CD3γ TIM3 DAP12 CD4 CD3ε TIM3 DAP12 CD4 FcγRI-γ TIM3 DAP12 CD4FcγRIII-γ TIM3 DAP12 CD4 FcεRIβ TIM3 DAP12 CD4 FcεRIγ TIM3 DAP12 CD4DAP10 TIM3 DAP12 CD4 DAP12 TIM3 DAP12 CD4 CD32 TIM3 DAP12 CD4 CD79a TIM3DAP12 CD4 CD79b TIM3 DAP12 b2c CD8 TIM3 DAP12 b2c CD3ζ TIM3 DAP12 b2cCD3δ TIM3 DAP12 b2c CD3γ TIM3 DAP12 b2c CD3ε TIM3 DAP12 b2c FcγRI-γ TIM3DAP12 b2c FcγRIII-γ TIM3 DAP12 b2c FcεRIβ TIM3 DAP12 b2c FcεRIγ TIM3DAP12 b2c DAP10 TIM3 DAP12 b2c DAP12 TIM3 DAP12 b2c CD32 TIM3 DAP12 b2cCD79a TIM3 DAP12 b2c CD79b TIM3 DAP12 CD137/41BB CD8 TIM3 DAP12CD137/41BB CD3ζ TIM3 DAP12 CD137/41BB CD3δ TIM3 DAP12 CD137/41BB CD3γTIM3 DAP12 CD137/41BB CD3ε TIM3 DAP12 CD137/41BB FcγRI-γ TIM3 DAP12CD137/41BB FcγRIII-γ TIM3 DAP12 CD137/41BB FcεRIβ TIM3 DAP12 CD137/41BBFcεRIγ TIM3 DAP12 CD137/41BB DAP10 TIM3 DAP12 CD137/41BB DAP12 TIM3DAP12 CD137/41BB CD32 TIM3 DAP12 CD137/41BB CD79a TIM3 DAP12 CD137/41BBCD79b TIM3 DAP12 ICOS CD8 TIM3 DAP12 ICOS CD3ζ TIM3 DAP12 ICOS CD3δ TIM3DAP12 ICOS CD3γ TIM3 DAP12 ICOS CD3ε TIM3 DAP12 ICOS FcγRI-γ TIM3 DAP12ICOS FcγRIII-γ TIM3 DAP12 ICOS FcεRIβ TIM3 DAP12 ICOS FcεRIγ TIM3 DAP12ICOS DAP10 TIM3 DAP12 ICOS DAP12 TIM3 DAP12 ICOS CD32 TIM3 DAP12 ICOSCD79a TIM3 DAP12 ICOS CD79b TIM3 DAP12 CD27 CD8 TIM3 DAP12 CD27 CD3ζTIM3 DAP12 CD27 CD3δ TIM3 DAP12 CD27 CD3γ TIM3 DAP12 CD27 CD3ε TIM3DAP12 CD27 FcγRI-γ TIM3 DAP12 CD27 FcγRIII-γ TIM3 DAP12 CD27 FcεRIβ TIM3DAP12 CD27 FcεRIγ TIM3 DAP12 CD27 DAP10 TIM3 DAP12 CD27 DAP12 TIM3 DAP12CD27 CD32 TIM3 DAP12 CD27 CD79a TIM3 DAP12 CD27 CD79b TIM3 DAP12 CD28δCD8 TIM3 DAP12 CD28δ CD3ζ TIM3 DAP12 CD28δ CD3δ TIM3 DAP12 CD28δ CD3γTIM3 DAP12 CD28δ CD3ε TIM3 DAP12 CD28δ FcγRI-γ TIM3 DAP12 CD28δFcγRIII-γ TIM3 DAP12 CD28δ FcεRIβ TIM3 DAP12 CD28δ FcεRIγ TIM3 DAP12CD28δ DAP10 TIM3 DAP12 CD28δ DAP12 TIM3 DAP12 CD28δ CD32 TIM3 DAP12CD28δ CD79a TIM3 DAP12 CD28δ CD79b TIM3 DAP12 CD80 CD8 TIM3 DAP12 CD80CD3ζ TIM3 DAP12 CD80 CD3δ TIM3 DAP12 CD80 CD3γ TIM3 DAP12 CD80 CD3ε TIM3DAP12 CD80 FcγRI-γ TIM3 DAP12 CD80 FcγRIII-γ TIM3 DAP12 CD80 FcεRIβ TIM3DAP12 CD80 FcεRIγ TIM3 DAP12 CD80 DAP10 TIM3 DAP12 CD80 DAP12 TIM3 DAP12CD80 CD32 TIM3 DAP12 CD80 CD79a TIM3 DAP12 CD80 CD79b TIM3 DAP12 CD86CD8 TIM3 DAP12 CD86 CD3ζ TIM3 DAP12 CD86 CD3δ TIM3 DAP12 CD86 CD3γ TIM3DAP12 CD86 CD3ε TIM3 DAP12 CD86 FcγRI-γ TIM3 DAP12 CD86 FcγRIII-γ TIM3DAP12 CD86 FcεRIβ TIM3 DAP12 CD86 FcεRIγ TIM3 DAP12 CD86 DAP10 TIM3DAP12 CD86 DAP12 TIM3 DAP12 CD86 CD32 TIM3 DAP12 CD86 CD79a TIM3 DAP12CD86 CD79b TIM3 DAP12 OX40 CD8 TIM3 DAP12 OX40 CD3ζ TIM3 DAP12 OX40 CD3δTIM3 DAP12 OX40 CD3γ TIM3 DAP12 OX40 CD3ε TIM3 DAP12 OX40 FcγRI-γ TIM3DAP12 OX40 FcγRIII-γ TIM3 DAP12 OX40 FcεRIβ TIM3 DAP12 OX40 FcεRIγ TIM3DAP12 OX40 DAP10 TIM3 DAP12 OX40 DAP12 TIM3 DAP12 OX40 CD32 TIM3 DAP12OX40 CD79a TIM3 DAP12 OX40 CD79b TIM3 DAP12 DAP10 CD8 TIM3 DAP12 DAP10CD3ζ TIM3 DAP12 DAP10 CD3δ TIM3 DAP12 DAP10 CD3γ TIM3 DAP12 DAP10 CD3εTIM3 DAP12 DAP10 FcγRI-γ TIM3 DAP12 DAP10 FcγRIII-γ TIM3 DAP12 DAP10FcεRIβ TIM3 DAP12 DAP10 FcεRIγ TIM3 DAP12 DAP10 DAP10 TIM3 DAP12 DAP10DAP12 TIM3 DAP12 DAP10 CD32 TIM3 DAP12 DAP10 CD79a TIM3 DAP12 DAP10CD79b TIM3 DAP12 DAP12 CD8 TIM3 DAP12 DAP12 CD3ζ TIM3 DAP12 DAP12 CD3δTIM3 DAP12 DAP12 CD3γ TIM3 DAP12 DAP12 CD3ε TIM3 DAP12 DAP12 FcγRI-γTIM3 DAP12 DAP12 FcγRIII-γ TIM3 DAP12 DAP12 FcεRIβ TIM3 DAP12 DAP12FcεRIγ TIM3 DAP12 DAP12 DAP10 TIM3 DAP12 DAP12 DAP12 TIM3 DAP12 DAP12CD32 TIM3 DAP12 DAP12 CD79a TIM3 DAP12 DAP12 CD79b TIM3 DAP12 MyD88 CD8TIM3 DAP12 MyD88 CD3ζ TIM3 DAP12 MyD88 CD3δ TIM3 DAP12 MyD88 CD3γ TIM3DAP12 MyD88 CD3ε TIM3 DAP12 MyD88 FcγRI-γ TIM3 DAP12 MyD88 FcγRIII-γTIM3 DAP12 MyD88 FcεRIβ TIM3 DAP12 MyD88 FcεRIγ TIM3 DAP12 MyD88 DAP10TIM3 DAP12 MyD88 DAP12 TIM3 DAP12 MyD88 CD32 TIM3 DAP12 MyD88 CD79a TIM3DAP12 MyD88 CD79b TIM3 DAP12 CD7 CD8 TIM3 DAP12 CD7 CD3ζ TIM3 DAP12 CD7CD3δ TIM3 DAP12 CD7 CD3γ TIM3 DAP12 CD7 CD3ε TIM3 DAP12 CD7 FcγRI-γ TIM3DAP12 CD7 FcγRIII-γ TIM3 DAP12 CD7 FcεRIβ TIM3 DAP12 CD7 FcεRIγ TIM3DAP12 CD7 DAP10 TIM3 DAP12 CD7 DAP12 TIM3 DAP12 CD7 CD32 TIM3 DAP12 CD7CD79a TIM3 DAP12 CD7 CD79b TIM3 DAP12 BTNL3 CD8 TIM3 DAP12 BTNL3 CD3ζTIM3 DAP12 BTNL3 CD3δ TIM3 DAP12 BTNL3 CD3γ TIM3 DAP12 BTNL3 CD3ε TIM3DAP12 BTNL3 FcγRI-γ TIM3 DAP12 BTNL3 FcγRIII-γ TIM3 DAP12 BTNL3 FcεRIβTIM3 DAP12 BTNL3 FcεRIγ TIM3 DAP12 BTNL3 DAP10 TIM3 DAP12 BTNL3 DAP12TIM3 DAP12 BTNL3 CD32 TIM3 DAP12 BTNL3 CD79a TIM3 DAP12 BTNL3 CD79b TIM3DAP12 NKG2D CD8 TIM3 DAP12 NKG2D CD3ζ TIM3 DAP12 NKG2D CD3δ TIM3 DAP12NKG2D CD3γ TIM3 DAP12 NKG2D CD3ε TIM3 DAP12 NKG2D FcγRI-γ TIM3 DAP12NKG2D FcγRIII-γ TIM3 DAP12 NKG2D FcεRIβ TIM3 DAP12 NKG2D FcεRIγ TIM3DAP12 NKG2D DAP10 TIM3 DAP12 NKG2D DAP12 TIM3 DAP12 NKG2D CD32 TIM3DAP12 NKG2D CD79a TIM3 DAP12 NKG2D CD79b TIM3 MyD88 CD28 CD8 TIM3 MyD88CD28 CD3ζ TIM3 MyD88 CD28 CD3δ TIM3 MyD88 CD28 CD3γ TIM3 MyD88 CD28 CD3εTIM3 MyD88 CD28 FcγRI-γ TIM3 MyD88 CD28 FcγRIII-γ TIM3 MyD88 CD28 FcεRIβTIM3 MyD88 CD28 FcεRIγ TIM3 MyD88 CD28 DAP10 TIM3 MyD88 CD28 DAP12 TIM3MyD88 CD28 CD32 TIM3 MyD88 CD28 CD79a TIM3 MyD88 CD28 CD79b TIM3 MyD88CD8 CD8 TIM3 MyD88 CD8 CD3ζ TIM3 MyD88 CD8 CD3δ TIM3 MyD88 CD8 CD3γ TIM3MyD88 CD8 CD3ε TIM3 MyD88 CD8 FcγRI-γ TIM3 MyD88 CD8 FcγRIII-γ TIM3MyD88 CD8 FcεRIβ TIM3 MyD88 CD8 FcεRIγ TIM3 MyD88 CD8 DAP10 TIM3 MyD88CD8 DAP12 TIM3 MyD88 CD8 CD32 TIM3 MyD88 CD8 CD79a TIM3 MyD88 CD8 CD79bTIM3 MyD88 CD4 CD8 TIM3 MyD88 CD4 CD3ζ TIM3 MyD88 CD4 CD3δ TIM3 MyD88CD4 CD3γ TIM3 MyD88 CD4 CD3ε TIM3 MyD88 CD4 FcγRI-γ TIM3 MyD88 CD4FcγRIII-γ TIM3 MyD88 CD4 FcεRIβ TIM3 MyD88 CD4 FcεRIγ TIM3 MyD88 CD4DAP10 TIM3 MyD88 CD4 DAP12 TIM3 MyD88 CD4 CD32 TIM3 MyD88 CD4 CD79a TIM3MyD88 CD4 CD79b TIM3 MyD88 b2c CD8 TIM3 MyD88 b2c CD3ζ TIM3 MyD88 b2cCD3δ TIM3 MyD88 b2c CD3γ TIM3 MyD88 b2c CD3ε TIM3 MyD88 b2c FcγRI-γ TIM3MyD88 b2c FcγRIII-γ TIM3 MyD88 b2c FcεRIβ TIM3 MyD88 b2c FcεRIγ TIM3MyD88 b2c DAP10 TIM3 MyD88 b2c DAP12 TIM3 MyD88 b2c CD32 TIM3 MyD88 b2cCD79a TIM3 MyD88 b2c CD79b TIM3 MyD88 CD137/41BB CD8 TIM3 MyD88CD137/41BB CD3ζ TIM3 MyD88 CD137/41BB CD3δ TIM3 MyD88 CD137/41BB CD3γTIM3 MyD88 CD137/41BB CD3ε TIM3 MyD88 CD137/41BB FcγRI-γ TIM3 MyD88CD137/41BB FcγRIII-γ TIM3 MyD88 CD137/41BB FcεRIβ TIM3 MyD88 CD137/41BBFcεRIγ TIM3 MyD88 CD137/41BB DAP10 TIM3 MyD88 CD137/41BB DAP12 TIM3MyD88 CD137/41BB CD32 TIM3 MyD88 CD137/41BB CD79a TIM3 MyD88 CD137/41BBCD79b TIM3 MyD88 ICOS CD8 TIM3 MyD88 ICOS CD3ζ TIM3 MyD88 ICOS CD3δ TIM3MyD88 ICOS CD3γ TIM3 MyD88 ICOS CD3ε TIM3 MyD88 ICOS FcγRI-γ TIM3 MyD88ICOS FcγRIII-γ TIM3 MyD88 ICOS FcεRIβ TIM3 MyD88 ICOS FcεRIγ TIM3 MyD88ICOS DAP10 TIM3 MyD88 ICOS DAP12 TIM3 MyD88 ICOS CD32 TIM3 MyD88 ICOSCD79a TIM3 MyD88 ICOS CD79b TIM3 MyD88 CD27 CD8 TIM3 MyD88 CD27 CD3ζTIM3 MyD88 CD27 CD3δ TIM3 MyD88 CD27 CD3γ TIM3 MyD88 CD27 CD3ε TIM3MyD88 CD27 FcγRI-γ TIM3 MyD88 CD27 FcγRIII-γ TIM3 MyD88 CD27 FcεRIβ TIM3MyD88 CD27 FcεRIγ TIM3 MyD88 CD27 DAP10 TIM3 MyD88 CD27 DAP12 TIM3 MyD88CD27 CD32 TIM3 MyD88 CD27 CD79a TIM3 MyD88 CD27 CD79b TIM3 MyD88 CD28δCD8 TIM3 MyD88 CD28δ CD3ζ TIM3 MyD88 CD28δ CD3δ TIM3 MyD88 CD28δ CD3γTIM3 MyD88 CD28δ CD3ε TIM3 MyD88 CD28δ FcγRI-γ TIM3 MyD88 CD28δFcγRIII-γ TIM3 MyD88 CD28δ FcεRIβ TIM3 MyD88 CD28δ FcεRIγ TIM3 MyD88CD28δ DAP10 TIM3 MyD88 CD28δ DAP12 TIM3 MyD88 CD28δ CD32 TIM3 MyD88CD28δ CD79a TIM3 MyD88 CD28δ CD79b TIM3 MyD88 CD80 CD8 TIM3 MyD88 CD80CD3ζ TIM3 MyD88 CD80 CD3δ TIM3 MyD88 CD80 CD3γ TIM3 MyD88 CD80 CD3ε TIM3MyD88 CD80 FcγRI-γ TIM3 MyD88 CD80 FcγRIII-γ TIM3 MyD88 CD80 FcεRIβ TIM3MyD88 CD80 FcεRIγ TIM3 MyD88 CD80 DAP10 TIM3 MyD88 CD80 DAP12 TIM3 MyD88CD80 CD32 TIM3 MyD88 CD80 CD79a TIM3 MyD88 CD80 CD79b TIM3 MyD88 CD86CD8 TIM3 MyD88 CD86 CD3ζ TIM3 MyD88 CD86 CD3δ TIM3 MyD88 CD86 CD3γ TIM3MyD88 CD86 CD3ε TIM3 MyD88 CD86 FcγRI-γ TIM3 MyD88 CD86 FcγRIII-γ TIM3MyD88 CD86 FcεRIβ TIM3 MyD88 CD86 FcεRIγ TIM3 MyD88 CD86 DAP10 TIM3MyD88 CD86 DAP12 TIM3 MyD88 CD86 CD32 TIM3 MyD88 CD86 CD79a TIM3 MyD88CD86 CD79b TIM3 MyD88 OX40 CD8 TIM3 MyD88 OX40 CD3ζ TIM3 MyD88 OX40 CD3δTIM3 MyD88 OX40 CD3γ TIM3 MyD88 OX40 CD3ε TIM3 MyD88 OX40 FcγRI-γ TIM3MyD88 OX40 FcγRIII-γ TIM3 MyD88 OX40 FcεRIβ TIM3 MyD88 OX40 FcεRIγ TIM3MyD88 OX40 DAP10 TIM3 MyD88 OX40 DAP12 TIM3 MyD88 OX40 CD32 TIM3 MyD88OX40 CD79a TIM3 MyD88 OX40 CD79b TIM3 MyD88 DAP10 CD8 TIM3 MyD88 DAP10CD3ζ TIM3 MyD88 DAP10 CD3δ TIM3 MyD88 DAP10 CD3γ TIM3 MyD88 DAP10 CD3εTIM3 MyD88 DAP10 FcγRI-γ TIM3 MyD88 DAP10 FcγRIII-γ TIM3 MyD88 DAP10FcεRIβ TIM3 MyD88 DAP10 FcεRIγ TIM3 MyD88 DAP10 DAP10 TIM3 MyD88 DAP10DAP12 TIM3 MyD88 DAP10 CD32 TIM3 MyD88 DAP10 CD79a TIM3 MyD88 DAP10CD79b TIM3 MyD88 DAP12 CD8 TIM3 MyD88 DAP12 CD3ζ TIM3 MyD88 DAP12 CD3δTIM3 MyD88 DAP12 CD3γ TIM3 MyD88 DAP12 CD3ε TIM3 MyD88 DAP12 FcγRI-γTIM3 MyD88 DAP12 FcγRIII-γ TIM3 MyD88 DAP12 FcεRIβ TIM3 MyD88 DAP12FcεRIγ TIM3 MyD88 DAP12 DAP10 TIM3 MyD88 DAP12 DAP12 TIM3 MyD88 DAP12CD32 TIM3 MyD88 DAP12 CD79a TIM3 MyD88 DAP12 CD79b TIM3 MyD88 MyD88 CD8TIM3 MyD88 MyD88 CD3ζ TIM3 MyD88 MyD88 CD3δ TIM3 MyD88 MyD88 CD3γ TIM3MyD88 MyD88 CD3ε TIM3 MyD88 MyD88 FcγRI-γ TIM3 MyD88 MyD88 FcγRIII-γTIM3 MyD88 MyD88 FcεRIβ TIM3 MyD88 MyD88 FcεRIγ TIM3 MyD88 MyD88 DAP10TIM3 MyD88 MyD88 DAP12 TIM3 MyD88 MyD88 CD32 TIM3 MyD88 MyD88 CD79a TIM3MyD88 MyD88 CD79b TIM3 MyD88 CD7 CD8 TIM3 MyD88 CD7 CD3ζ TIM3 MyD88 CD7CD3δ TIM3 MyD88 CD7 CD3γ TIM3 MyD88 CD7 CD3ε TIM3 MyD88 CD7 FcγRI-γ TIM3MyD88 CD7 FcγRIII-γ TIM3 MyD88 CD7 FcεRIβ TIM3 MyD88 CD7 FcεRIγ TIM3MyD88 CD7 DAP10 TIM3 MyD88 CD7 DAP12 TIM3 MyD88 CD7 CD32 TIM3 MyD88 CD7CD79a TIM3 MyD88 CD7 CD79b TIM3 MyD88 BTNL3 CD8 TIM3 MyD88 BTNL3 CD3ζTIM3 MyD88 BTNL3 CD3δ TIM3 MyD88 BTNL3 CD3γ TIM3 MyD88 BTNL3 CD3ε TIM3MyD88 BTNL3 FcγRI-γ TIM3 MyD88 BTNL3 FcγRIII-γ TIM3 MyD88 BTNL3 FcεRIβTIM3 MyD88 BTNL3 FcεRIγ TIM3 MyD88 BTNL3 DAP10 TIM3 MyD88 BTNL3 DAP12TIM3 MyD88 BTNL3 CD32 TIM3 MyD88 BTNL3 CD79a TIM3 MyD88 BTNL3 CD79b TIM3MyD88 NKG2D CD8 TIM3 MyD88 NKG2D CD3ζ TIM3 MyD88 NKG2D CD3δ TIM3 MyD88NKG2D CD3γ TIM3 MyD88 NKG2D CD3ε TIM3 MyD88 NKG2D FcγRI-γ TIM3 MyD88NKG2D FcγRIII-γ TIM3 MyD88 NKG2D FcεRIβ TIM3 MyD88 NKG2D FcεRIγ TIM3MyD88 NKG2D DAP10 TIM3 MyD88 NKG2D DAP12 TIM3 MyD88 NKG2D CD32 TIM3MyD88 NKG2D CD79a TIM3 MyD88 NKG2D CD79b TIM3 CD7 CD28 CD8 TIM3 CD7 CD28CD3ζ TIM3 CD7 CD28 CD3δ TIM3 CD7 CD28 CD3γ TIM3 CD7 CD28 CD3ε TIM3 CD7CD28 FcγRI-γ TIM3 CD7 CD28 FcγRIII-γ TIM3 CD7 CD28 FcεRIβ TIM3 CD7 CD28FcεRIγ TIM3 CD7 CD28 DAP10 TIM3 CD7 CD28 DAP12 TIM3 CD7 CD28 CD32 TIM3CD7 CD28 CD79a TIM3 CD7 CD28 CD79b TIM3 CD7 CD8 CD8 TIM3 CD7 CD8 CD3ζTIM3 CD7 CD8 CD3δ TIM3 CD7 CD8 CD3γ TIM3 CD7 CD8 CD3ε TIM3 CD7 CD8FcγRI-γ TIM3 CD7 CD8 FcγRIII-γ TIM3 CD7 CD8 FcεRIβ TIM3 CD7 CD8 FcεRIγTIM3 CD7 CD8 DAP10 TIM3 CD7 CD8 DAP12 TIM3 CD7 CD8 CD32 TIM3 CD7 CD8CD79a TIM3 CD7 CD8 CD79b TIM3 CD7 CD4 CD8 TIM3 CD7 CD4 CD3ζ TIM3 CD7 CD4CD3δ TIM3 CD7 CD4 CD3γ TIM3 CD7 CD4 CD3ε TIM3 CD7 CD4 FcγRI-γ TIM3 CD7CD4 FcγRIII-γ TIM3 CD7 CD4 FcεRIβ TIM3 CD7 CD4 FcεRIγ TIM3 CD7 CD4 DAP10TIM3 CD7 CD4 DAP12 TIM3 CD7 CD4 CD32 TIM3 CD7 CD4 CD79a TIM3 CD7 CD4CD79b TIM3 CD7 b2c CD8 TIM3 CD7 b2c CD3ζ TIM3 CD7 b2c CD3δ TIM3 CD7 b2cCD3γ TIM3 CD7 b2c CD3ε TIM3 CD7 b2c FcγRI-γ TIM3 CD7 b2c FcγRIII-γ TIM3CD7 b2c FcεRIβ TIM3 CD7 b2c FcεRIγ TIM3 CD7 b2c DAP10 TIM3 CD7 b2c DAP12TIM3 CD7 b2c CD32 TIM3 CD7 b2c CD79a TIM3 CD7 b2c CD79b TIM3 CD7CD137/41BB CD8 TIM3 CD7 CD137/41BB CD3ζ TIM3 CD7 CD137/41BB CD3δ TIM3CD7 CD137/41BB CD3γ TIM3 CD7 CD137/41BB CD3ε TIM3 CD7 CD137/41BB FcγRI-γTIM3 CD7 CD137/41BB FcγRIII-γ TIM3 CD7 CD137/41BB FcεRIβ TIM3 CD7CD137/41BB FcεRIγ TIM3 CD7 CD137/41BB DAP10 TIM3 CD7 CD137/41BB DAP12TIM3 CD7 CD137/41BB CD32 TIM3 CD7 CD137/41BB CD79a TIM3 CD7 CD137/41BBCD79b TIM3 CD7 ICOS CD8 TIM3 CD7 ICOS CD3ζ TIM3 CD7 ICOS CD3δ TIM3 CD7ICOS CD3γ TIM3 CD7 ICOS CD3ε TIM3 CD7 ICOS FcγRI-γ TIM3 CD7 ICOSFcγRIII-γ TIM3 CD7 ICOS FcεRIβ TIM3 CD7 ICOS FcεRIγ TIM3 CD7 ICOS DAP10TIM3 CD7 ICOS DAP12 TIM3 CD7 ICOS CD32 TIM3 CD7 ICOS CD79a TIM3 CD7 ICOSCD79b TIM3 CD7 CD27 CD8 TIM3 CD7 CD27 CD3ζ TIM3 CD7 CD27 CD3δ TIM3 CD7CD27 CD3γ TIM3 CD7 CD27 CD3ε TIM3 CD7 CD27 FcγRI-γ TIM3 CD7 CD27FcγRIII-γ TIM3 CD7 CD27 FcεRIβ TIM3 CD7 CD27 FcεRIγ TIM3 CD7 CD27 DAP10TIM3 CD7 CD27 DAP12 TIM3 CD7 CD27 CD32 TIM3 CD7 CD27 CD79a TIM3 CD7 CD27CD79b TIM3 CD7 CD28δ CD8 TIM3 CD7 CD28δ CD3ζ TIM3 CD7 CD28δ CD3δ TIM3CD7 CD28δ CD3γ TIM3 CD7 CD28δ CD3ε TIM3 CD7 CD28δ FcγRI-γ TIM3 CD7 CD28δFcγRIII-γ TIM3 CD7 CD28δ FcεRIβ TIM3 CD7 CD28δ FcεRIγ TIM3 CD7 CD28δDAP10 TIM3 CD7 CD28δ DAP12 TIM3 CD7 CD28δ CD32 TIM3 CD7 CD28δ CD79a TIM3CD7 CD28δ CD79b TIM3 CD7 CD80 CD8 TIM3 CD7 CD80 CD3ζ TIM3 CD7 CD80 CD3δTIM3 CD7 CD80 CD3γ TIM3 CD7 CD80 CD3ε TIM3 CD7 CD80 FcγRI-γ TIM3 CD7CD80 FcγRIII-γ TIM3 CD7 CD80 FcεRIβ TIM3 CD7 CD80 FcεRIγ TIM3 CD7 CD80DAP10 TIM3 CD7 CD80 DAP12 TIM3 CD7 CD80 CD32 TIM3 CD7 CD80 CD79a TIM3CD7 CD80 CD79b TIM3 CD7 CD86 CD8 TIM3 CD7 CD86 CD3ζ TIM3 CD7 CD86 CD3δTIM3 CD7 CD86 CD3γ TIM3 CD7 CD86 CD3ε TIM3 CD7 CD86 FcγRI-γ TIM3 CD7CD86 FcγRIII-γ TIM3 CD7 CD86 FcεRIβ TIM3 CD7 CD86 FcεRIγ TIM3 CD7 CD86DAP10 TIM3 CD7 CD86 DAP12 TIM3 CD7 CD86 CD32 TIM3 CD7 CD86 CD79a TIM3CD7 CD86 CD79b TIM3 CD7 OX40 CD8 TIM3 CD7 OX40 CD3ζ TIM3 CD7 OX40 CD3δTIM3 CD7 OX40 CD3γ TIM3 CD7 OX40 CD3ε TIM3 CD7 OX40 FcγRI-γ TIM3 CD7OX40 FcγRIII-γ TIM3 CD7 OX40 FcεRIβ TIM3 CD7 OX40 FcεRIγ TIM3 CD7 OX40DAP10 TIM3 CD7 OX40 DAP12 TIM3 CD7 OX40 CD32 TIM3 CD7 OX40 CD79a TIM3CD7 OX40 CD79b TIM3 CD7 DAP10 CD8 TIM3 CD7 DAP10 CD3ζ TIM3 CD7 DAP10CD3δ TIM3 CD7 DAP10 CD3γ TIM3 CD7 DAP10 CD3ε TIM3 CD7 DAP10 FcγRI-γ TIM3CD7 DAP10 FcγRIII-γ TIM3 CD7 DAP10 FcεRIβ TIM3 CD7 DAP10 FcεRIγ TIM3 CD7DAP10 DAP10 TIM3 CD7 DAP10 DAP12 TIM3 CD7 DAP10 CD32 TIM3 CD7 DAP10CD79a TIM3 CD7 DAP10 CD79b TIM3 CD7 DAP12 CD8 TIM3 CD7 DAP12 CD3ζ TIM3CD7 DAP12 CD3δ TIM3 CD7 DAP12 CD3γ TIM3 CD7 DAP12 CD3ε TIM3 CD7 DAP12FcγRI-γ TIM3 CD7 DAP12 FcγRIII-γ TIM3 CD7 DAP12 FcεRIβ TIM3 CD7 DAP12FcεRIγ TIM3 CD7 DAP12 DAP10 TIM3 CD7 DAP12 DAP12 TIM3 CD7 DAP12 CD32TIM3 CD7 DAP12 CD79a TIM3 CD7 DAP12 CD79b TIM3 CD7 MyD88 CD8 TIM3 CD7MyD88 CD3ζ TIM3 CD7 MyD88 CD3δ TIM3 CD7 MyD88 CD3γ TIM3 CD7 MyD88 CD3εTIM3 CD7 MyD88 FcγRI-γ TIM3 CD7 MyD88 FcγRIII-γ TIM3 CD7 MyD88 FcεRIβTIM3 CD7 MyD88 FcεRIγ TIM3 CD7 MyD88 DAP10 TIM3 CD7 MyD88 DAP12 TIM3 CD7MyD88 CD32 TIM3 CD7 MyD88 CD79a TIM3 CD7 MyD88 CD79b TIM3 CD7 CD7 CD8TIM3 CD7 CD7 CD3ζ TIM3 CD7 CD7 CD3δ TIM3 CD7 CD7 CD3γ TIM3 CD7 CD7 CD3εTIM3 CD7 CD7 FcγRI-γ TIM3 CD7 CD7 FcγRIII-γ TIM3 CD7 CD7 FcεRIβ TIM3 CD7CD7 FcεRIγ TIM3 CD7 CD7 DAP10 TIM3 CD7 CD7 DAP12 TIM3 CD7 CD7 CD32 TIM3CD7 CD7 CD79a TIM3 CD7 CD7 CD79b TIM3 CD7 BTNL3 CD8 TIM3 CD7 BTNL3 CD3ζTIM3 CD7 BTNL3 CD3δ TIM3 CD7 BTNL3 CD3γ TIM3 CD7 BTNL3 CD3ε TIM3 CD7BTNL3 FcγRI-γ TIM3 CD7 BTNL3 FcγRIII-γ TIM3 CD7 BTNL3 FcεRIβ TIM3 CD7BTNL3 FcεRIγ TIM3 CD7 BTNL3 DAP10 TIM3 CD7 BTNL3 DAP12 TIM3 CD7 BTNL3CD32 TIM3 CD7 BTNL3 CD79a TIM3 CD7 BTNL3 CD79b TIM3 CD7 NKG2D CD8 TIM3CD7 NKG2D CD3ζ TIM3 CD7 NKG2D CD3δ TIM3 CD7 NKG2D CD3γ TIM3 CD7 NKG2DCD3ε TIM3 CD7 NKG2D FcγRI-γ TIM3 CD7 NKG2D FcγRIII-γ TIM3 CD7 NKG2DFcεRIβ TIM3 CD7 NKG2D FcεRIγ TIM3 CD7 NKG2D DAP10 TIM3 CD7 NKG2D DAP12TIM3 CD7 NKG2D CD32 TIM3 CD7 NKG2D CD79a TIM3 CD7 NKG2D CD79b TIM3 BTNL3CD28 CD8 TIM3 BTNL3 CD28 CD3ζ TIM3 BTNL3 CD28 CD3δ TIM3 BTNL3 CD28 CD3γTIM3 BTNL3 CD28 CD3ε TIM3 BTNL3 CD28 FcγRI-γ TIM3 BTNL3 CD28 FcγRIII-γTIM3 BTNL3 CD28 FcεRIβ TIM3 BTNL3 CD28 FcεRIγ TIM3 BTNL3 CD28 DAP10 TIM3BTNL3 CD28 DAP12 TIM3 BTNL3 CD28 CD32 TIM3 BTNL3 CD28 CD79a TIM3 BTNL3CD28 CD79b TIM3 BTNL3 CD8 CD8 TIM3 BTNL3 CD8 CD3ζ TIM3 BTNL3 CD8 CD3δTIM3 BTNL3 CD8 CD3γ TIM3 BTNL3 CD8 CD3ε TIM3 BTNL3 CD8 FcγRI-γ TIM3BTNL3 CD8 FcγRIII-γ TIM3 BTNL3 CD8 FcεRIβ TIM3 BTNL3 CD8 FcεRIγ TIM3BTNL3 CD8 DAP10 TIM3 BTNL3 CD8 DAP12 TIM3 BTNL3 CD8 CD32 TIM3 BTNL3 CD8CD79a TIM3 BTNL3 CD8 CD79b TIM3 BTNL3 CD4 CD8 TIM3 BTNL3 CD4 CD3ζ TIM3BTNL3 CD4 CD3δ TIM3 BTNL3 CD4 CD3γ TIM3 BTNL3 CD4 CD3ε TIM3 BTNL3 CD4FcγRI-γ TIM3 BTNL3 CD4 FcγRIII-γ TIM3 BTNL3 CD4 FcεRIβ TIM3 BTNL3 CD4FcεRIγ TIM3 BTNL3 CD4 DAP10 TIM3 BTNL3 CD4 DAP12 TIM3 BTNL3 CD4 CD32TIM3 BTNL3 CD4 CD79a TIM3 BTNL3 CD4 CD79b TIM3 BTNL3 b2c CD8 TIM3 BTNL3b2c CD3ζ TIM3 BTNL3 b2c CD3δ TIM3 BTNL3 b2c CD3γ TIM3 BTNL3 b2c CD3εTIM3 BTNL3 b2c FcγRI-γ TIM3 BTNL3 b2c FcγRIII-γ TIM3 BTNL3 b2c FcεRIβTIM3 BTNL3 b2c FcεRIγ TIM3 BTNL3 b2c DAP10 TIM3 BTNL3 b2c DAP12 TIM3BTNL3 b2c CD32 TIM3 BTNL3 b2c CD79a TIM3 BTNL3 b2c CD79b TIM3 BTNL3CD137/41BB CD8 TIM3 BTNL3 CD137/41BB CD3ζ TIM3 BTNL3 CD137/41BB CD3δTIM3 BTNL3 CD137/41BB CD3γ TIM3 BTNL3 CD137/41BB CD3ε TIM3 BTNL3CD137/41BB FcγRI-γ TIM3 BTNL3 CD137/41BB FcγRIII-γ TIM3 BTNL3 CD137/41BBFcεRIβ TIM3 BTNL3 CD137/41BB FcεRIγ TIM3 BTNL3 CD137/41BB DAP10 TIM3BTNL3 CD137/41BB DAP12 TIM3 BTNL3 CD137/41BB CD32 TIM3 BTNL3 CD137/41BBCD79a TIM3 BTNL3 CD137/41BB CD79b TIM3 BTNL3 ICOS CD8 TIM3 BTNL3 ICOSCD3ζ TIM3 BTNL3 ICOS CD3δ TIM3 BTNL3 ICOS CD3γ TIM3 BTNL3 ICOS CD3ε TIM3BTNL3 ICOS FcγRI-γ TIM3 BTNL3 ICOS FcγRIII-γ TIM3 BTNL3 ICOS FcεRIβ TIM3BTNL3 ICOS FcεRIγ TIM3 BTNL3 ICOS DAP10 TIM3 BTNL3 ICOS DAP12 TIM3 BTNL3ICOS CD32 TIM3 BTNL3 ICOS CD79a TIM3 BTNL3 ICOS CD79b TIM3 BTNL3 CD27CD8 TIM3 BTNL3 CD27 CD3ζ TIM3 BTNL3 CD27 CD3δ TIM3 BTNL3 CD27 CD3γ TIM3BTNL3 CD27 CD3ε TIM3 BTNL3 CD27 FcγRI-γ TIM3 BTNL3 CD27 FcγRIII-γ TIM3BTNL3 CD27 FcεRIβ TIM3 BTNL3 CD27 FcεRIγ TIM3 BTNL3 CD27 DAP10 TIM3BTNL3 CD27 DAP12 TIM3 BTNL3 CD27 CD32 TIM3 BTNL3 CD27 CD79a TIM3 BTNL3CD27 CD79b TIM3 BTNL3 CD28δ CD8 TIM3 BTNL3 CD28δ CD3ζ TIM3 BTNL3 CD28δCD3δ TIM3 BTNL3 CD28δ CD3γ TIM3 BTNL3 CD28δ CD3ε TIM3 BTNL3 CD28δFcγRI-γ TIM3 BTNL3 CD28δ FcγRIII-γ TIM3 BTNL3 CD28δ FcεRIβ TIM3 BTNL3CD28δ FcεRIγ TIM3 BTNL3 CD28δ DAP10 TIM3 BTNL3 CD28δ DAP12 TIM3 BTNL3CD28δ CD32 TIM3 BTNL3 CD28δ CD79a TIM3 BTNL3 CD28δ CD79b TIM3 BTNL3 CD80CD8 TIM3 BTNL3 CD80 CD3ζ TIM3 BTNL3 CD80 CD3δ TIM3 BTNL3 CD80 CD3γ TIM3BTNL3 CD80 CD3ε TIM3 BTNL3 CD80 FcγRI-γ TIM3 BTNL3 CD80 FcγRIII-γ TIM3BTNL3 CD80 FcεRIβ TIM3 BTNL3 CD80 FcεRIγ TIM3 BTNL3 CD80 DAP10 TIM3BTNL3 CD80 DAP12 TIM3 BTNL3 CD80 CD32 TIM3 BTNL3 CD80 CD79a TIM3 BTNL3CD80 CD79b TIM3 BTNL3 CD86 CD8 TIM3 BTNL3 CD86 CD3ζ TIM3 BTNL3 CD86 CD3δTIM3 BTNL3 CD86 CD3γ TIM3 BTNL3 CD86 CD3ε TIM3 BTNL3 CD86 FcγRI-γ TIM3BTNL3 CD86 FcγRIII-γ TIM3 BTNL3 CD86 FcεRIβ TIM3 BTNL3 CD86 FcεRIγ TIM3BTNL3 CD86 DAP10 TIM3 BTNL3 CD86 DAP12 TIM3 BTNL3 CD86 CD32 TIM3 BTNL3CD86 CD79a TIM3 BTNL3 CD86 CD79b TIM3 BTNL3 OX40 CD8 TIM3 BTNL3 OX40CD3ζ TIM3 BTNL3 OX40 CD3δ TIM3 BTNL3 OX40 CD3γ TIM3 BTNL3 OX40 CD3ε TIM3BTNL3 OX40 FcγRI-γ TIM3 BTNL3 OX40 FcγRIII-γ TIM3 BTNL3 OX40 FcεRIβ TIM3BTNL3 OX40 FcεRIγ TIM3 BTNL3 OX40 DAP10 TIM3 BTNL3 OX40 DAP12 TIM3 BTNL3OX40 CD32 TIM3 BTNL3 OX40 CD79a TIM3 BTNL3 OX40 CD79b TIM3 BTNL3 DAP10CD8 TIM3 BTNL3 DAP10 CD3ζ TIM3 BTNL3 DAP10 CD3δ TIM3 BTNL3 DAP10 CD3γTIM3 BTNL3 DAP10 CD3ε TIM3 BTNL3 DAP10 FcγRI-γ TIM3 BTNL3 DAP10FcγRIII-γ TIM3 BTNL3 DAP10 FcεRIβ TIM3 BTNL3 DAP10 FcεRIγ TIM3 BTNL3DAP10 DAP10 TIM3 BTNL3 DAP10 DAP12 TIM3 BTNL3 DAP10 CD32 TIM3 BTNL3DAP10 CD79a TIM3 BTNL3 DAP10 CD79b TIM3 BTNL3 DAP12 CD8 TIM3 BTNL3 DAP12CD3ζ TIM3 BTNL3 DAP12 CD3δ TIM3 BTNL3 DAP12 CD3γ TIM3 BTNL3 DAP12 CD3εTIM3 BTNL3 DAP12 FcγRI-γ TIM3 BTNL3 DAP12 FcγRIII-γ TIM3 BTNL3 DAP12FcεRIβ TIM3 BTNL3 DAP12 FcεRIγ TIM3 BTNL3 DAP12 DAP10 TIM3 BTNL3 DAP12DAP12 TIM3 BTNL3 DAP12 CD32 TIM3 BTNL3 DAP12 CD79a TIM3 BTNL3 DAP12CD79b TIM3 BTNL3 MyD88 CD8 TIM3 BTNL3 MyD88 CD3ζ TIM3 BTNL3 MyD88 CD3δTIM3 BTNL3 MyD88 CD3γ TIM3 BTNL3 MyD88 CD3ε TIM3 BTNL3 MyD88 FcγRI-γTIM3 BTNL3 MyD88 FcγRIII-γ TIM3 BTNL3 MyD88 FcεRIβ TIM3 BTNL3 MyD88FcεRIγ TIM3 BTNL3 MyD88 DAP10 TIM3 BTNL3 MyD88 DAP12 TIM3 BTNL3 MyD88CD32 TIM3 BTNL3 MyD88 CD79a TIM3 BTNL3 MyD88 CD79b TIM3 BTNL3 CD7 CD8TIM3 BTNL3 CD7 CD3ζ TIM3 BTNL3 CD7 CD3δ TIM3 BTNL3 CD7 CD3γ TIM3 BTNL3CD7 CD3ε TIM3 BTNL3 CD7 FcγRI-γ TIM3 BTNL3 CD7 FcγRIII-γ TIM3 BTNL3 CD7FcεRIβ TIM3 BTNL3 CD7 FcεRIγ TIM3 BTNL3 CD7 DAP10 TIM3 BTNL3 CD7 DAP12TIM3 BTNL3 CD7 CD32 TIM3 BTNL3 CD7 CD79a TIM3 BTNL3 CD7 CD79b TIM3 BTNL3BTNL3 CD8 TIM3 BTNL3 BTNL3 CD3ζ TIM3 BTNL3 BTNL3 CD3δ TIM3 BTNL3 BTNL3CD3γ TIM3 BTNL3 BTNL3 CD3ε TIM3 BTNL3 BTNL3 FcγRI-γ TIM3 BTNL3 BTNL3FcγRIII-γ TIM3 BTNL3 BTNL3 FcεRIβ TIM3 BTNL3 BTNL3 FcεRIγ TIM3 BTNL3BTNL3 DAP10 TIM3 BTNL3 BTNL3 DAP12 TIM3 BTNL3 BTNL3 CD32 TIM3 BTNL3BTNL3 CD79a TIM3 BTNL3 BTNL3 CD79b TIM3 BTNL3 NKG2D CD8 TIM3 BTNL3 NKG2DCD3ζ TIM3 BTNL3 NKG2D CD3δ TIM3 BTNL3 NKG2D CD3γ TIM3 BTNL3 NKG2D CD3εTIM3 BTNL3 NKG2D FcγRI-γ TIM3 BTNL3 NKG2D FcγRIII-γ TIM3 BTNL3 NKG2DFcεRIβ TIM3 BTNL3 NKG2D FcεRIγ TIM3 BTNL3 NKG2D DAP10 TIM3 BTNL3 NKG2DDAP12 TIM3 BTNL3 NKG2D CD32 TIM3 BTNL3 NKG2D CD79a TIM3 BTNL3 NKG2DCD79b TIM3 NKG2D CD28 CD8 TIM3 NKG2D CD28 CD3ζ TIM3 NKG2D CD28 CD3δ TIM3NKG2D CD28 CD3γ TIM3 NKG2D CD28 CD3ε TIM3 NKG2D CD28 FcγRI-γ TIM3 NKG2DCD28 FcγRIII-γ TIM3 NKG2D CD28 FcεRIβ TIM3 NKG2D CD28 FcεRIγ TIM3 NKG2DCD28 DAP10 TIM3 NKG2D CD28 DAP12 TIM3 NKG2D CD28 CD32 TIM3 NKG2D CD28CD79a TIM3 NKG2D CD28 CD79b TIM3 NKG2D CD8 CD8 TIM3 NKG2D CD8 CD3ζ TIM3NKG2D CD8 CD3δ TIM3 NKG2D CD8 CD3γ TIM3 NKG2D CD8 CD3ε TIM3 NKG2D CD8FcγRI-γ TIM3 NKG2D CD8 FcγRIII-γ TIM3 NKG2D CD8 FcεRIβ TIM3 NKG2D CD8FcεRIγ TIM3 NKG2D CD8 DAP10 TIM3 NKG2D CD8 DAP12 TIM3 NKG2D CD8 CD32TIM3 NKG2D CD8 CD79a TIM3 NKG2D CD8 CD79b TIM3 NKG2D CD4 CD8 TIM3 NKG2DCD4 CD3ζ TIM3 NKG2D CD4 CD3δ TIM3 NKG2D CD4 CD3γ TIM3 NKG2D CD4 CD3εTIM3 NKG2D CD4 FcγRI-γ TIM3 NKG2D CD4 FcγRIII-γ TIM3 NKG2D CD4 FcεRIβTIM3 NKG2D CD4 FcεRIγ TIM3 NKG2D CD4 DAP10 TIM3 NKG2D CD4 DAP12 TIM3NKG2D CD4 CD32 TIM3 NKG2D CD4 CD79a TIM3 NKG2D CD4 CD79b TIM3 NKG2D b2cCD8 TIM3 NKG2D b2c CD3ζ TIM3 NKG2D b2c CD3δ TIM3 NKG2D b2c CD3γ TIM3NKG2D b2c CD3ε TIM3 NKG2D b2c FcγRI-γ TIM3 NKG2D b2c FcγRIII-γ TIM3NKG2D b2c FcεRIβ TIM3 NKG2D b2c FcεRIγ TIM3 NKG2D b2c DAP10 TIM3 NKG2Db2c DAP12 TIM3 NKG2D b2c CD32 TIM3 NKG2D b2c CD79a TIM3 NKG2D b2c CD79bTIM3 NKG2D CD137/41BB CD8 TIM3 NKG2D CD137/41BB CD3ζ TIM3 NKG2DCD137/41BB CD3δ TIM3 NKG2D CD137/41BB CD3γ TIM3 NKG2D CD137/41BB CD3εTIM3 NKG2D CD137/41BB FcγRI-γ TIM3 NKG2D CD137/41BB FcγRIII-γ TIM3 NKG2DCD137/41BB FcεRIβ TIM3 NKG2D CD137/41BB FcεRIγ TIM3 NKG2D CD137/41BBDAP10 TIM3 NKG2D CD137/41BB DAP12 TIM3 NKG2D CD137/41BB CD32 TIM3 NKG2DCD137/41BB CD79a TIM3 NKG2D CD137/41BB CD79b TIM3 NKG2D ICOS CD8 TIM3NKG2D ICOS CD3ζ TIM3 NKG2D ICOS CD3δ TIM3 NKG2D ICOS CD3γ TIM3 NKG2DICOS CD3ε TIM3 NKG2D ICOS FcγRI-γ TIM3 NKG2D ICOS FcγRIII-γ TIM3 NKG2DICOS FcεRIβ TIM3 NKG2D ICOS FcεRIγ TIM3 NKG2D ICOS DAP10 TIM3 NKG2D ICOSDAP12 TIM3 NKG2D ICOS CD32 TIM3 NKG2D ICOS CD79a TIM3 NKG2D ICOS CD79bTIM3 NKG2D CD27 CD8 TIM3 NKG2D CD27 CD3ζ TIM3 NKG2D CD27 CD3δ TIM3 NKG2DCD27 CD3γ TIM3 NKG2D CD27 CD3ε TIM3 NKG2D CD27 FcγRI-γ TIM3 NKG2D CD27FcγRIII-γ TIM3 NKG2D CD27 FcεRIβ TIM3 NKG2D CD27 FcεRIγ TIM3 NKG2D CD27DAP10 TIM3 NKG2D CD27 DAP12 TIM3 NKG2D CD27 CD32 TIM3 NKG2D CD27 CD79aTIM3 NKG2D CD27 CD79b TIM3 NKG2D CD28δ CD8 TIM3 NKG2D CD28δ CD3ζ TIM3NKG2D CD28δ CD3δ TIM3 NKG2D CD28δ CD3γ TIM3 NKG2D CD28δ CD3ε TIM3 NKG2DCD28δ FcγRI-γ TIM3 NKG2D CD28δ FcγRIII-γ TIM3 NKG2D CD28δ FcεRIβ TIM3NKG2D CD28δ FcεRIγ TIM3 NKG2D CD28δ DAP10 TIM3 NKG2D CD28δ DAP12 TIM3NKG2D CD28δ CD32 TIM3 NKG2D CD28δ CD79a TIM3 NKG2D CD28δ CD79b TIM3NKG2D CD80 CD8 TIM3 NKG2D CD80 CD3ζ TIM3 NKG2D CD80 CD3δ TIM3 NKG2D CD80CD3γ TIM3 NKG2D CD80 CD3ε TIM3 NKG2D CD80 FcγRI-γ TIM3 NKG2D CD80FcγRIII-γ TIM3 NKG2D CD80 FcεRIβ TIM3 NKG2D CD80 FcεRIγ TIM3 NKG2D CD80DAP10 TIM3 NKG2D CD80 DAP12 TIM3 NKG2D CD80 CD32 TIM3 NKG2D CD80 CD79aTIM3 NKG2D CD80 CD79b TIM3 NKG2D CD86 CD8 TIM3 NKG2D CD86 CD3ζ TIM3NKG2D CD86 CD3δ TIM3 NKG2D CD86 CD3γ TIM3 NKG2D CD86 CD3ε TIM3 NKG2DCD86 FcγRI-γ TIM3 NKG2D CD86 FcγRIII-γ TIM3 NKG2D CD86 FcεRIβ TIM3 NKG2DCD86 FcεRIγ TIM3 NKG2D CD86 DAP10 TIM3 NKG2D CD86 DAP12 TIM3 NKG2D CD86CD32 TIM3 NKG2D CD86 CD79a TIM3 NKG2D CD86 CD79b TIM3 NKG2D OX40 CD8TIM3 NKG2D OX40 CD3ζ TIM3 NKG2D OX40 CD3δ TIM3 NKG2D OX40 CD3γ TIM3NKG2D OX40 CD3ε TIM3 NKG2D OX40 FcγRI-γ TIM3 NKG2D OX40 FcγRIII-γ TIM3NKG2D OX40 FcεRIβ TIM3 NKG2D OX40 FcεRIγ TIM3 NKG2D OX40 DAP10 TIM3NKG2D OX40 DAP12 TIM3 NKG2D OX40 CD32 TIM3 NKG2D OX40 CD79a TIM3 NKG2DOX40 CD79b TIM3 NKG2D DAP10 CD8 TIM3 NKG2D DAP10 CD3ζ TIM3 NKG2D DAP10CD3δ TIM3 NKG2D DAP10 CD3γ TIM3 NKG2D DAP10 CD3ε TIM3 NKG2D DAP10FcγRI-γ TIM3 NKG2D DAP10 FcγRIII-γ TIM3 NKG2D DAP10 FcεRIβ TIM3 NKG2DDAP10 FcεRIγ TIM3 NKG2D DAP10 DAP10 TIM3 NKG2D DAP10 DAP12 TIM3 NKG2DDAP10 CD32 TIM3 NKG2D DAP10 CD79a TIM3 NKG2D DAP10 CD79b TIM3 NKG2DDAP12 CD8 TIM3 NKG2D DAP12 CD3ζ TIM3 NKG2D DAP12 CD3δ TIM3 NKG2D DAP12CD3γ TIM3 NKG2D DAP12 CD3ε TIM3 NKG2D DAP12 FcγRI-γ TIM3 NKG2D DAP12FcγRIII-γ TIM3 NKG2D DAP12 FcεRIβ TIM3 NKG2D DAP12 FcεRIγ TIM3 NKG2DDAP12 DAP10 TIM3 NKG2D DAP12 DAP12 TIM3 NKG2D DAP12 CD32 TIM3 NKG2DDAP12 CD79a TIM3 NKG2D DAP12 CD79b TIM3 NKG2D MyD88 CD8 TIM3 NKG2D MyD88CD3ζ TIM3 NKG2D MyD88 CD3δ TIM3 NKG2D MyD88 CD3γ TIM3 NKG2D MyD88 CD3εTIM3 NKG2D MyD88 FcγRI-γ TIM3 NKG2D MyD88 FcγRIII-γ TIM3 NKG2D MyD88FcεRIβ TIM3 NKG2D MyD88 FcεRIγ TIM3 NKG2D MyD88 DAP10 TIM3 NKG2D MyD88DAP12 TIM3 NKG2D MyD88 CD32 TIM3 NKG2D MyD88 CD79a TIM3 NKG2D MyD88CD79b TIM3 NKG2D CD7 CD8 TIM3 NKG2D CD7 CD3ζ TIM3 NKG2D CD7 CD3δ TIM3NKG2D CD7 CD3γ TIM3 NKG2D CD7 CD3ε TIM3 NKG2D CD7 FcγRI-γ TIM3 NKG2D CD7FcγRIII-γ TIM3 NKG2D CD7 FcεRIβ TIM3 NKG2D CD7 FcεRIγ TIM3 NKG2D CD7DAP10 TIM3 NKG2D CD7 DAP12 TIM3 NKG2D CD7 CD32 TIM3 NKG2D CD7 CD79a TIM3NKG2D CD7 CD79b TIM3 NKG2D BTNL3 CD8 TIM3 NKG2D BTNL3 CD3ζ TIM3 NKG2DBTNL3 CD3δ TIM3 NKG2D BTNL3 CD3γ TIM3 NKG2D BTNL3 CD3ε TIM3 NKG2D BTNL3FcγRI-γ TIM3 NKG2D BTNL3 FcγRIII-γ TIM3 NKG2D BTNL3 FcεRIβ TIM3 NKG2DBTNL3 FcεRIγ TIM3 NKG2D BTNL3 DAP10 TIM3 NKG2D BTNL3 DAP12 TIM3 NKG2DBTNL3 CD32 TIM3 NKG2D BTNL3 CD79a TIM3 NKG2D BTNL3 CD79b TIM3 NKG2DNKG2D CD8 TIM3 NKG2D NKG2D CD3ζ TIM3 NKG2D NKG2D CD3δ TIM3 NKG2D NKG2DCD3γ TIM3 NKG2D NKG2D CD3ε TIM3 NKG2D NKG2D FcγRI-γ TIM3 NKG2D NKG2DFcγRIII-γ TIM3 NKG2D NKG2D FcεRIβ TIM3 NKG2D NKG2D FcεRIγ TIM3 NKG2DNKG2D DAP10 TIM3 NKG2D NKG2D DAP12 TIM3 NKG2D NKG2D CD32 TIM3 NKG2DNKG2D CD79a TIM3 NKG2D NKG2D CD79b

TABLE 4 CARs lacking Co-Simulatory Signal (for dual CAR approach) ScFvCo-stimulatory Signal Signal Domain TIM3 none CD8 TIM3 none CD3ζ TIM3none CD3δ TIM3 none CD3γ TIM3 none CD3ε TIM3 none FcγRI-γ TIM3 noneFcγRIII-γ TIM3 none FcεRIβ TIM3 none FcεRIγ TIM3 none DAP10 TIM3 noneDAP12 TIM3 none CD32 TIM3 none CD79a TIM3 none CD8 TIM3 none CD3ζ TIM3none CD3δ TIM3 none CD3γ TIM3 none CD3ε TIM3 none FcγRI-γ

TABLE 5 CARs lacking Signal Domain (for dual CAR approach) ScFvCo-stimulatory Signal Signal Domain TIM3 CD28 none TIM3 CD8 none TIM3CD4 none TIM3 b2c none TIM3 CD137/41BB none TIM3 ICOS none TIM3 CD27none TIM3 CD28δ none TIM3 CD80 none TIM3 CD86 none TIM3 OX40 none TIM3DAP10 none TIM3 MyD88 none TIM3 CD7 none TIM3 DAP12 none TIM3 MyD88 noneTIM3 CD7 none TIM3 BTNL3 none TIM3 NKG2D none

TABLE 6 Third Generation CARs lacking Signal Domain (for dual CARapproach) Co-stimulatory Co-stimulatory Signal ScFv Signal Signal DomainTIM3 CD28 CD28 none TIM3 CD28 CD8 none TIM3 CD28 CD4 none TIM3 CD28 b2cnone TIM3 CD28 CD137/41BB none TIM3 CD28 ICOS none TIM3 CD28 CD27 noneTIM3 CD28 CD28δ none TIM3 CD28 CD80 none TIM3 CD28 CD86 none TIM3 CD28OX40 none TIM3 CD28 DAP10 none TIM3 CD28 MyD88 none TIM3 CD28 CD7 noneTIM3 CD28 DAP12 none TIM3 CD28 MyD88 none TIM3 CD28 CD7 none TIM3 CD8CD28 none TIM3 CD8 CD8 none TIM3 CD8 CD4 none TIM3 CD8 b2c none TIM3 CD8CD137/41BB none TIM3 CD8 ICOS none TIM3 CD8 CD27 none TIM3 CD8 CD28δnone TIM3 CD8 CD80 none TIM3 CD8 CD86 none TIM3 CD8 OX40 none TIM3 CD8DAP10 none TIM3 CD8 MyD88 none TIM3 CD8 CD7 none TIM3 CD8 DAP12 noneTIM3 CD8 MyD88 none TIM3 CD8 CD7 none TIM3 CD4 CD28 none TIM3 CD4 CD8none TIM3 CD4 CD4 none TIM3 CD4 b2c none TIM3 CD4 CD137/41BB none TIM3CD4 ICOS none TIM3 CD4 CD27 none TIM3 CD4 CD28δ none TIM3 CD4 CD80 noneTIM3 CD4 CD86 none TIM3 CD4 OX40 none TIM3 CD4 DAP10 none TIM3 CD4 MyD88none TIM3 CD4 CD7 none TIM3 CD4 DAP12 none TIM3 CD4 MyD88 none TIM3 CD4CD7 none TIM3 b2c CD28 none TIM3 b2c CD8 none TIM3 b2c CD4 none TIM3 b2cb2c none TIM3 b2c CD137/41BB none TIM3 b2c ICOS none TIM3 b2c CD27 noneTIM3 b2c CD28δ none TIM3 b2c CD80 none TIM3 b2c CD86 none TIM3 b2c OX40none TIM3 b2c DAP10 none TIM3 b2c MyD88 none TIM3 b2c CD7 none TIM3 b2cDAP12 none TIM3 b2c MyD88 none TIM3 b2c CD7 none TIM3 CD137/41BB CD28none TIM3 CD137/41BB CD8 none TIM3 CD137/41BB CD4 none TIM3 CD137/41BBb2c none TIM3 CD137/41BB CD137/41BB none TIM3 CD137/41BB ICOS none TIM3CD137/41BB CD27 none TIM3 CD137/41BB CD28δ none TIM3 CD137/41BB CD80none TIM3 CD137/41BB CD86 none TIM3 CD137/41BB OX40 none TIM3 CD137/41BBDAP10 none TIM3 CD137/41BB MyD88 none TIM3 CD137/41BB CD7 none TIM3CD137/41BB DAP12 none TIM3 CD137/41BB MyD88 none TIM3 CD137/41BB CD7none TIM3 ICOS CD28 none TIM3 ICOS CD8 none TIM3 ICOS CD4 none TIM3 ICOSb2c none TIM3 ICOS CD137/41BB none TIM3 ICOS ICOS none TIM3 ICOS CD27none TIM3 ICOS CD28δ none TIM3 ICOS CD80 none TIM3 ICOS CD86 none TIM3ICOS OX40 none TIM3 ICOS DAP10 none TIM3 ICOS MyD88 none TIM3 ICOS CD7none TIM3 ICOS DAP12 none TIM3 ICOS MyD88 none TIM3 ICOS CD7 none TIM3ICOS CD28 none TIM3 ICOS CD8 none TIM3 ICOS CD4 none TIM3 ICOS b2c noneTIM3 ICOS CD137/41BB none TIM3 ICOS ICOS none TIM3 ICOS CD27 none TIM3ICOS CD28δ none TIM3 ICOS CD80 none TIM3 ICOS CD86 none TIM3 ICOS OX40none TIM3 ICOS DAP10 none TIM3 ICOS MyD88 none TIM3 ICOS CD7 none TIM3ICOS DAP12 none TIM3 ICOS MyD88 none TIM3 ICOS CD7 none TIM3 CD27 CD28none TIM3 CD27 CD8 none TIM3 CD27 CD4 none TIM3 CD27 b2c none TIM3 CD27CD137/41BB none TIM3 CD27 ICOS none TIM3 CD27 CD27 none TIM3 CD27 CD28δnone TIM3 CD27 CD80 none TIM3 CD27 CD86 none TIM3 CD27 OX40 none TIM3CD27 DAP10 none TIM3 CD27 MyD88 none TIM3 CD27 CD7 none TIM3 CD27 DAP12none TIM3 CD27 MyD88 none TIM3 CD27 CD7 none TIM3 CD28δ CD28 none TIM3CD28δ CD8 none TIM3 CD28δ CD4 none TIM3 CD28δ b2c none TIM3 CD28δCD137/41BB none TIM3 CD28δ ICOS none TIM3 CD28δ CD27 none TIM3 CD28δCD28δ none TIM3 CD28δ CD80 none TIM3 CD28δ CD86 none TIM3 CD28δ OX40none TIM3 CD28δ DAP10 none TIM3 CD28δ MyD88 none TIM3 CD28δ CD7 noneTIM3 CD28δ DAP12 none TIM3 CD28δ MyD88 none TIM3 CD28δ CD7 none TIM3CD80 CD28 none TIM3 CD80 CD8 none TIM3 CD80 CD4 none TIM3 CD80 b2c noneTIM3 CD80 CD137/41BB none TIM3 CD80 ICOS none TIM3 CD80 CD27 none TIM3CD80 CD28δ none TIM3 CD80 CD80 none TIM3 CD80 CD86 none TIM3 CD80 OX40none TIM3 CD80 DAP10 none TIM3 CD80 MyD88 none TIM3 CD80 CD7 none TIM3CD80 DAP12 none TIM3 CD80 MyD88 none TIM3 CD80 CD7 none TIM3 CD86 CD28none TIM3 CD86 CD8 none TIM3 CD86 CD4 none TIM3 CD86 b2c none TIM3 CD86CD137/41BB none TIM3 CD86 ICOS none TIM3 CD86 CD27 none TIM3 CD86 CD28δnone TIM3 CD86 CD80 none TIM3 CD86 CD86 none TIM3 CD86 OX40 none TIM3CD86 DAP10 none TIM3 CD86 MyD88 none TIM3 CD86 CD7 none TIM3 CD86 DAP12none TIM3 CD86 MyD88 none TIM3 CD86 CD7 none TIM3 OX40 CD28 none TIM3OX40 CD8 none TIM3 OX40 CD4 none TIM3 OX40 b2c none TIM3 OX40 CD137/41BBnone TIM3 OX40 ICOS none TIM3 OX40 CD27 none TIM3 OX40 CD28δ none TIM3OX40 CD80 none TIM3 OX40 CD86 none TIM3 OX40 OX40 none TIM3 OX40 DAP10none TIM3 OX40 MyD88 none TIM3 OX40 CD7 none TIM3 OX40 DAP12 none TIM3OX40 MyD88 none TIM3 OX40 CD7 none TIM3 DAP10 CD28 none TIM3 DAP10 CD8none TIM3 DAP10 CD4 none TIM3 DAP10 b2c none TIM3 DAP10 CD137/41BB noneTIM3 DAP10 ICOS none TIM3 DAP10 CD27 none TIM3 DAP10 CD28δ none TIM3DAP10 CD80 none TIM3 DAP10 CD86 none TIM3 DAP10 OX40 none TIM3 DAP10DAP10 none TIM3 DAP10 MyD88 none TIM3 DAP10 CD7 none TIM3 DAP10 DAP12none TIM3 DAP10 MyD88 none TIM3 DAP10 CD7 none TIM3 DAP12 CD28 none TIM3DAP12 CD8 none TIM3 DAP12 CD4 none TIM3 DAP12 b2c none TIM3 DAP12CD137/41BB none TIM3 DAP12 ICOS none TIM3 DAP12 CD27 none TIM3 DAP12CD28δ none TIM3 DAP12 CD80 none TIM3 DAP12 CD86 none TIM3 DAP12 OX40none TIM3 DAP12 DAP10 none TIM3 DAP12 MyD88 none TIM3 DAP12 CD7 noneTIM3 DAP12 DAP12 none TIM3 DAP12 MyD88 none TIM3 DAP12 CD7 none TIM3MyD88 CD28 none TIM3 MyD88 CD8 none TIM3 MyD88 CD4 none TIM3 MyD88 b2cnone TIM3 MyD88 CD137/41BB none TIM3 MyD88 ICOS none TIM3 MyD88 CD27none TIM3 MyD88 CD28δ none TIM3 MyD88 CD80 none TIM3 MyD88 CD86 noneTIM3 MyD88 OX40 none TIM3 MyD88 DAP10 none TIM3 MyD88 MyD88 none TIM3MyD88 CD7 none TIM3 MyD88 DAP12 none TIM3 MyD88 MyD88 none TIM3 MyD88CD7 none TIM3 CD7 CD28 none TIM3 CD7 CD8 none TIM3 CD7 CD4 none TIM3 CD7b2c none TIM3 CD7 CD137/41BB none TIM3 CD7 ICOS none TIM3 CD7 CD27 noneTIM3 CD7 CD28δ none TIM3 CD7 CD80 none TIM3 CD7 CD86 none TIM3 CD7 OX40none TIM3 CD7 DAP10 none TIM3 CD7 MyD88 none TIM3 CD7 CD7 none TIM3 CD7DAP12 none TIM3 CD7 MyD88 none TIM3 CD7 CD7 none TIM3 BTNL3 CD28 noneTIM3 BTNL3 CD8 none TIM3 BTNL3 CD4 none TIM3 BTNL3 b2c none TIM3 BTNL3CD137/41BB none TIM3 BTNL3 ICOS none TIM3 BTNL3 CD27 none TIM3 BTNL3CD28δ none TIM3 BTNL3 CD80 none TIM3 BTNL3 CD86 none TIM3 BTNL3 OX40none TIM3 BTNL3 DAP10 none TIM3 BTNL3 MyD88 none TIM3 BTNL3 CD7 noneTIM3 BTNL3 DAP12 none TIM3 BTNL3 MyD88 none TIM3 BTNL3 CD7 none TIM3NKG2D CD28 none TIM3 NKG2D CD8 none TIM3 NKG2D CD4 none TIM3 NKG2D b2cnone TIM3 NKG2D CD137/41BB none TIM3 NKG2D ICOS none TIM3 NKG2D CD27none TIM3 NKG2D CD28δ none TIM3 NKG2D CD80 none TIM3 NKG2D CD86 noneTIM3 NKG2D OX40 none TIM3 NKG2D DAP10 none TIM3 NKG2D MyD88 none TIM3NKG2D CD7 none TIM3 NKG2D DAP12 none TIM3 NKG2D MyD88 none TIM3 NKG2DCD7 none

In some embodiments, the anti-TIM3 binding agent is single chainvariable fragment (scFv) antibody. The affinity/specificity of ananti-TIM3 scFv is driven in large part by specific sequences withincomplementarity determining regions (CDRs) in the heavy (V_(H)) andlight (V_(L)) chain. Each V_(H) and V_(L) sequence will have three CDRs(CDR1, CDR2, CDR3).

In some cases, the anti-TIM3 V_(H) domain comprises the amino acidsequence QVTLKESGPGILQPSQTLSLTCSFSGFSLSTSNMAVSWIRQPSGKGLEWLALIYWDDDKRYNPSLKSRLTISKDTSRNQVFLKITSVDAADTATYYCVRSQLLRFAYWGQGTL VTVSA (SEQ IDNO:1), or a fragment or variant thereof able to bind TIM3.

In some cases, the anti-TIM3 V_(H) domain comprises the amino acidsequence QVQLQQPGAELVKPGASVKLSCKASGYTGTSYYMYWVKQRPGQGLEWIGGINPSNGGTNFNEKFKSKATLTVDKSSSTAYMQLSSLTSEDSAVYYCTTAYFDYWGQGTTL TVSS (SEQ IDNO:2), or a fragment or variant thereof able to bind TIM3.

In some cases, the anti-TIM3 V_(L) domain comprises the amino acidsequence DIQMTQSSSYLSVSLGGRVTITCKASDHINNWLAWYQQKPGNAPRLLISGATSLETGVPSRFSGRGSGKDYTLSITSLQTEDVATYYCQQYWSTPVTFGAGTKLELKAAA (SEQ ID NO:3), ora fragment or variant thereof able to bind TIM3.

In some cases, the anti-TIM3 V_(L) domain comprises the amino acidsequence DIVMTQSPATLSVTPGDRVSLSCRASQSISDYLHWYQQKSHESPRLLIKYASQSISGIPSRFSGSGSGSDFTLSINSVEPEDVGVYYCQNGHSFPRTFGGGTKLEIKAAA (SEQ ID NO:4), or afragment or variant thereof able to bind TIM3.

In some cases, the anti-TIM3 V_(L) domain comprises the amino acidsequence EIVLTQSPAITAASLGQKVTITCSASSSVSYMHWYQQKSGTSPKPWIYEISKLASGVPARFSGSGSGTSYSLTISSMEAEDAAIYYCQQWNYPLYTFGGGTKLEIKAAA (SEQ ID NO:5), or afragment or variant thereof able to bind TIM3.

In some cases, the anti-TIM3 V_(L) domain comprises the amino acidsequence QIVLTQSPAIMSASPGEKVTMSCSASPGEKVTMSCSASSSLTYMYWFQQKPGSSPKPWIYRTSNLASGVPARFSGSGSGTSYSLTISSMEAEDAATYTCQQYHSYPPTFGG GTKLEIKAAA (SEQID NO:6), or a fragment or variant thereof able to bind TIM3.

In some cases, the anti-TIM3 V_(L) domain comprises the amino acidsequence XIVXTQSPAXXSXSXGXXVTXXCXASXSXXXYXXWYQQKXGXSPXXXIXXXSXLXSGVPXRFSGSGSGXXYXLXIXSXEXEDXAXYYCQXXSXPXTFGGGTKLEIKAAA (SEQ ID NO:7),wherein “X” is any amino acid or no amino acid, or a fragment or variantthereof able to bind TIM3. Also disclosed are other consensus sequencesbased on the alignments shown in FIGS. 9 and 10, e.g. based onconservative substitutions at variable residues.

In some embodiments, the disclosed CAR comprises a hinge and/ortransmembrane domain derived from CD8. For example, the CAR can comprisethe amino acid sequence

(SEQ ID NO: 8) FVPVFLPAKPTTTPAPRPPTPAPTIASQPLSLRPEACRPAAGGAVHTRGLDFACDIYIWAPLAGTCGVLLLSLVITLYCNHRNR.

In some embodiments, the disclosed CAR comprises a hinge and/ortransmembrane domain derived from CD28. For example, the CAR cancomprise the amino acid sequence

(SEQ ID NO: 9) VMYPPPYLDNEKSNGTIIHVKGKHLCPSPLFPGPSKPFWVLVVVGGVLACYSLLVTVAFIIFWV.

In some embodiments, the disclosed CAR comprises a costimulatory domainderived from CD28. For example, the CAR can comprise the amino acidsequence RSKRSRLLHSDYMNMTPRRPGPTRKHYQPYAPPRDFAAYRS (SEQ ID NO: 10).

In some embodiments, the disclosed CAR comprises a costimulatory domainderived from 4-1 BB. For example, the CAR can comprise the amino acidsequence RFSWKRGRKKLLYIFKQPFMRPVQTTQEEDGCSCRFPEEEEGGCEL (SEQ ID NO:11).

In some embodiments, the disclosed CAR comprises an intracellularsignaling domain derived from CD3 zeta (CD3ζ). For example, the CAR cancomprise the amino acid sequence

(SEQ ID NO: 12) RVKFSRSADAPAYQQGQNQLYNELNLGRREEYDVLDKRRGRDPEMGGKPRRKNPQEGLYNELQKDKMAEAYSEIGMKGERRRGKGHDGLYQGLSTATKDT YDALHMQALPPR.

In some embodiments, the disclosed CAR comprises a linker between theV_(H) and V_(L) domains having the amino acid sequenceGSTSGSGKPGSGEGSTKG (SEQ ID NO:13).

In some embodiments, the disclosed CAR comprises a signal peptide havingthe amino acid sequence MVLLVTSLLLCELPHPAFLLIP (SEQ ID NO:14).

In some embodiments, the anti-TIM3 binding agent is derived from naturalantibodies, such as monoclonal antibodies. In some cases, the antibodyis human. In some cases, the antibody has undergone an alteration torender it less immunogenic when administered to humans. For example, thealteration comprises one or more techniques selected from the groupconsisting of chimerization, humanization, CDR-grafting, deimmunization,and mutation of framework amino acids to correspond to the closest humangermline sequence.

Also disclosed are bi-specific CARs that target TIM3 and at least oneadditional tumor antigen. Also disclosed are CARs designed to work onlyin conjunction with another CAR that binds a different antigen, such asa tumor antigen. For example, in these embodiments, the endodomain ofthe disclosed CAR can contain only an signaling domain (SD) or aco-stimulatory signaling region (CSR), but not both. The second CAR (orendogenous T-cell) provides the missing signal if it is activated. Forexample, if the disclosed CAR contains an SD but not a CSR, then theimmune effector cell containing this CAR is only activated if anotherCAR (or T-cell) containing a CSR binds its respective antigen. Likewise,if the disclosed CAR contains a CSR but not a SD, then the immuneeffector cell containing this CAR is only activated if another CAR (orT-cell) containing an SD binds its respective antigen.

Tumor antigens are proteins that are produced by tumor cells that elicitan immune response, particularly T-cell mediated immune responses. Theadditional antigen binding domain can be an antibody or a natural ligandof the tumor antigen. The selection of the additional antigen bindingdomain will depend on the particular type of cancer to be treated. Tumorantigens are well known in the art and include, for example, aglioma-associated antigen, carcinoembryonic antigen (CEA), EGFRvIII,IL-IIRa, IL-13Ra, EGFR, FAP, B7H3, Kit, CA LX, CS-1, MUC1, BCMA,bcr-abl, HER2, β-human chorionic gonadotropin, alphafetoprotein (AFP),ALK, CD19, CD123, cyclin BI, lectin-reactive AFP, Fos-related antigen 1,ADRB3, thyroglobulin, EphA2, RAGE-1, RUI, RU2, SSX2, AKAP-4, LCK,OY-TESI, PAX5, SART3, CLL-1, fucosyl GM1, GloboH, MN-CA IX, EPCAM,EVT6-AML, TGS5, human telomerase reverse transcriptase, plysialic acid,PLAC1, RUI, RU2 (AS), intestinal carboxyl esterase, lewisY, sLe, LY6K,mut hsp70-2, M-CSF, MYCN, RhoC, TRP-2, CYPIBI, BORIS, prostase,prostate-specific antigen (PSA), PAX3, PAP, NY-ESO-1, LAGE-la, LMP2,NCAM, p53, p53 mutant, Ras mutant, gplOO, prostein, OR51E2, PANX3, PSMA,PSCA, Her2/neu, hTERT, HMWMAA, HAVCRI, VEGFR2, PDGFR-beta, survivin andtelomerase, legumain, HPV E6,E7, sperm protein 17, SSEA-4, tyrosinase,TARP, WTI, prostate-carcinoma tumor antigen-1 (PCTA-1), ML-IAP, MAGE,MAGE-AI, MAD-CT-1, MAD-CT-2, MelanA/MART 1, XAGE1, ELF2M, ERG (TMPRSS2ETS fusion gene), NA17, neutrophil elastase, sarcoma transiocationbreakpoints, NY-BR-1, ephnnB2, CD20, CD22, CD24, CD30, CD33, CD38,CD44v6, CD97, CD99, CD171, CD179a, androgen receptor, FAP, insulingrowth factor (IGF)-I, IGFII, IGF-I receptor, GD2, o-acetyl-GD2, GD3,GM3, GPRC5D, GPR20, CXORF61, folate receptor (FRa), folate receptorbeta, ROR1, FIt3, TAG72, TN Ag, Tie 2, TEM1, TEM7R, CLDN6, TSHR, UPK2,and mesothelin. In a preferred embodiment, the tumor antigen is selectedfrom the group consisting of folate receptor (FRa), mesothelin,EGFRvIII, IL-13Ra, CD123, CD19, CD33, BCMA, GD2, CLL-1, CA-IX, MUCI,HER2, CD99, and any combination thereof.

Non-limiting examples of tumor antigens include the following:Differentiation antigens such as tyrosinase, TRP-1, TRP-2 andtumor-specific multilineage antigens such as MAGE-1, MAGE-3, BAGE,GAGE-1, GAGE-2, pi 5; overexpressed embryonic antigens such as CEAoverexpressed oncogenes and mutated tumor-suppressor genes such as p53,Ras, HER-2/neu; unique tumor antigens resulting from chromosomaltranslocations; such as BCR-ABL, E2A-PRL, H4-RET, IGH-IGK, MYL-RAR; andviral antigens, such as the Epstein Barr virus antigens EBVA and thehuman papillomavirus (HPV) antigens E6 and E7. Other large,protein-based antigens include TSP-180, MAGE-4, MAGE-5, MAGE-6, RAGE,NY-ESO, pI85erbB2, pI80erbB-3, c-met, nm-23H1, PSA, TIM3, CA 19-9, CA72-4, CAM 17.1, NuMa, K-ras, beta-Catenin, CDK4, Mum-I, p 15, p 16,43-9F, 5T4, 791Tgp72, alpha-fetoprotein, beta-HCG, BCA225, BTAA, CA 125,CA 15-3CA 27.29BCAA, CA 195, CA 242, CA-50, CAM43, CD68P1, CO-029,FGF-5, G250, Ga733EpCAM, HTgp-175, M344, MA-50, MG7-Ag, MOV18, NB/70K,NY-CO-1, RCASI, SDCCAGI 6, TA-90\ac-2 binding protein\cyclophilmC-associated protein, TAAL6, TAG72, TLP, TPS, GPC3, MUC16, LMP1, EBMA-1,BARF-1, CSI, CD319, HER1, B7H6, LICAM, IL6, and MET.

Nucleic Acids and Vectors

Also disclosed are polynucleotides and polynucleotide vectors encodingthe disclosed TIM3-specific CARs that allow expression of theTIM3-specific CARs in the disclosed immune effector cells.

Nucleic acid sequences encoding the disclosed CARs, and regions thereof,can be obtained using recombinant methods known in the art, such as, forexample by screening libraries from cells expressing the gene, byderiving the gene from a vector known to include the same, or byisolating directly from cells and tissues containing the same, usingstandard techniques. Alternatively, the gene of interest can be producedsynthetically, rather than cloned.

Expression of nucleic acids encoding CARs is typically achieved byoperably linking a nucleic acid encoding the CAR polypeptide to apromoter, and incorporating the construct into an expression vector.Typical cloning vectors contain transcription and translationterminators, initiation sequences, and promoters useful for regulationof the expression of the desired nucleic acid sequence.

The disclosed nucleic acid can be cloned into a number of types ofvectors. For example, the nucleic acid can be cloned into a vectorincluding, but not limited to a plasmid, a phagemid, a phage derivative,an animal virus, and a cosmid. Vectors of particular interest includeexpression vectors, replication vectors, probe generation vectors, andsequencing vectors.

Further, the expression vector may be provided to a cell in the form ofa viral vector. Viral vector technology is well known in the art and isdescribed, for example, in Sambrook et al. (2001, Molecular Cloning: ALaboratory Manual, Cold Spring Harbor Laboratory, New York), and inother virology and molecular biology manuals. Viruses, which are usefulas vectors include, but are not limited to, retroviruses, adenoviruses,adeno-associated viruses, herpes viruses, and lentiviruses. In general,a suitable vector contains an origin of replication functional in atleast one organism, a promoter sequence, convenient restrictionendonuclease sites, and one or more selectable markers. In someembodiments, the polynucleotide vectors are lentiviral or retroviralvectors.

A number of viral based systems have been developed for gene transferinto mammalian cells. For example, retroviruses provide a convenientplatform for gene delivery systems. A selected gene can be inserted intoa vector and packaged in retroviral particles using techniques known inthe art. The recombinant virus can then be isolated and delivered tocells of the subject either in vivo or ex vivo.

One example of a suitable promoter is the immediate earlycytomegalovirus (CMV) promoter sequence. This promoter sequence is astrong constitutive promoter sequence capable of driving high levels ofexpression of any polynucleotide sequence operatively linked thereto.Another example of a suitable promoter is Elongation Growth Factor-1α(EF-1α). However, other constitutive promoter sequences may also beused, including, but not limited to the simian virus 40 (SV40) earlypromoter, MND (myeloproliferative sarcoma virus) promoter, mouse mammarytumor virus (MMTV), human immunodeficiency virus (HIV) long terminalrepeat (LTR) promoter, MoMuLV promoter, an avian leukemia viruspromoter, an Epstein-Barr virus immediate early promoter, a Rous sarcomavirus promoter, as well as human gene promoters such as, but not limitedto, the actin promoter, the myosin promoter, the hemoglobin promoter,and the creatine kinase promoter. The promoter can alternatively be aninducible promoter. Examples of inducible promoters include, but are notlimited to a metallothionine promoter, a glucocorticoid promoter, aprogesterone promoter, and a tetracycline promoter.

Additional promoter elements, e.g., enhancers, regulate the frequency oftranscriptional initiation. Typically, these are located in the region30-110 bp upstream of the start site, although a number of promotershave recently been shown to contain functional elements downstream ofthe start site as well. The spacing between promoter elements frequentlyis flexible, so that promoter function is preserved when elements areinverted or moved relative to one another.

In order to assess the expression of a CAR polypeptide or portionsthereof, the expression vector to be introduced into a cell can alsocontain either a selectable marker gene or a reporter gene or both tofacilitate identification and selection of expressing cells from thepopulation of cells sought to be transfected or infected through viralvectors. In other aspects, the selectable marker may be carried on aseparate piece of DNA and used in a co-transfection procedure. Bothselectable markers and reporter genes may be flanked with appropriateregulatory sequences to enable expression in the host cells. Usefulselectable markers include, for example, antibiotic-resistance genes.

Reporter genes are used for identifying potentially transfected cellsand for evaluating the functionality of regulatory sequences. Ingeneral, a reporter gene is a gene that is not present in or expressedby the recipient organism or tissue and that encodes a polypeptide whoseexpression is manifested by some easily detectable property, e.g.,enzymatic activity. Expression of the reporter gene is assayed at asuitable time after the DNA has been introduced into the recipientcells. Suitable reporter genes may include genes encoding luciferase,beta-galactosidase, chloramphenicol acetyl transferase, secretedalkaline phosphatase, or the green fluorescent protein gene. Suitableexpression systems are well known and may be prepared using knowntechniques or obtained commercially. In general, the construct with theminimal 5′ flanking region showing the highest level of expression ofreporter gene is identified as the promoter. Such promoter regions maybe linked to a reporter gene and used to evaluate agents for the abilityto modulate promoter-driven transcription.

Methods of introducing and expressing genes into a cell are known in theart. In the context of an expression vector, the vector can be readilyintroduced into a host cell, e.g., mammalian, bacterial, yeast, orinsect cell by any method in the art. For example, the expression vectorcan be transferred into a host cell by physical, chemical, or biologicalmeans.

Physical methods for introducing a polynucleotide into a host cellinclude calcium phosphate precipitation, lipofection, particlebombardment, microinjection, electroporation, and the like. Methods forproducing cells comprising vectors and/or exogenous nucleic acids arewell-known in the art. See, for example, Sambrook et al. (2001,Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory,New York).

Biological methods for introducing a polynucleotide of interest into ahost cell include the use of DNA and RNA vectors. Viral vectors, andespecially retroviral vectors, have become the most widely used methodfor inserting genes into mammalian, e.g., human cells.

Chemical means for introducing a polynucleotide into a host cell includecolloidal dispersion systems, such as macromolecule complexes,nanocapsules, microspheres, beads, and lipid-based systems includingoil-in-water emulsions, micelles, mixed micelles, and liposomes. Anexemplary colloidal system for use as a delivery vehicle in vitro and invivo is a liposome (e.g., an artificial membrane vesicle).

In the case where a non-viral delivery system is utilized, an exemplarydelivery vehicle is a liposome. In another aspect, the nucleic acid maybe associated with a lipid. The nucleic acid associated with a lipid maybe encapsulated in the aqueous interior of a liposome, interspersedwithin the lipid bilayer of a liposome, attached to a liposome via alinking molecule that is associated with both the liposome and theoligonucleotide, entrapped in a liposome, complexed with a liposome,dispersed in a solution containing a lipid, mixed with a lipid, combinedwith a lipid, contained as a suspension in a lipid, contained orcomplexed with a micelle, or otherwise associated with a lipid. Lipid,lipid/DNA or lipid/expression vector associated compositions are notlimited to any particular structure in solution. For example, they maybe present in a bilayer structure, as micelles, or with a “collapsed”structure. They may also simply be interspersed in a solution, possiblyforming aggregates that are not uniform in size or shape. Lipids arefatty substances which may be naturally occurring or synthetic lipids.For example, lipids include the fatty droplets that naturally occur inthe cytoplasm as well as the class of compounds which contain long-chainaliphatic hydrocarbons and their derivatives, such as fatty acids,alcohols, amines, amino alcohols, and aldehydes. Lipids suitable for usecan be obtained from commercial sources. For example, dimyristylphosphatidyicholine (“DMPC”) can be obtained from Sigma, St. Louis, Mo.;dicetyl phosphate (“DCP”) can be obtained from K & K Laboratories(Plainview, N.Y.); cholesterol (“Choi”) can be obtained fromCalbiochem-Behring; dimyristyl phosphatidylglycerol (“DMPG”) and otherlipids may be obtained from Avanti Polar Lipids, Inc, (Birmingham,Ala.).

Immune Effector Cells

Also disclosed are immune effector cells that are engineered to expressthe disclosed CARs (also referred to herein as “CAR-T cells.” Thesecells are preferably obtained from the subject to be treated (i.e. areautologous). However, in some embodiments, immune effector cell lines ordonor effector cells (allogeneic) are used. Immune effector cells can beobtained from a number of sources, including peripheral bloodmononuclear cells, bone marrow, lymph node tissue, cord blood, thymustissue, tissue from a site of infection, ascites, pleural effusion,spleen tissue, and tumors. Immune effector cells can be obtained fromblood collected from a subject using any number of techniques known tothe skilled artisan, such as Ficoll™ separation. For example, cells fromthe circulating blood of an individual may be obtained by apheresis. Insome embodiments, immune effector cells are isolated from peripheralblood lymphocytes by lysing the red blood cells and depleting themonocytes, for example, by centrifugation through a PERCOLL™ gradient orby counterflow centrifugal elutriation. A specific subpopulation ofimmune effector cells can be further isolated by positive or negativeselection techniques. For example, immune effector cells can be isolatedusing a combination of antibodies directed to surface markers unique tothe positively selected cells, e.g., by incubation withantibody-conjugated beads for a time period sufficient for positiveselection of the desired immune effector cells. Alternatively,enrichment of immune effector cells population can be accomplished bynegative selection using a combination of antibodies directed to surfacemarkers unique to the negatively selected cells.

In some embodiments, the immune effector cells comprise any leukocyteinvolved in defending the body against infectious disease and foreignmaterials. For example, the immune effector cells can compriselymphocytes, monocytes, macrophages, dentritic cells, mast cells,neutrophils, basophils, eosinophils, or any combinations thereof. Forexample, the immune effector cells can comprise T lymphocytes.

T cells or T lymphocytes can be distinguished from other lymphocytes,such as B cells and natural killer cells (NK cells), by the presence ofa T-cell receptor (TCR) on the cell surface. They are called T cellsbecause they mature in the thymus (although some also mature in thetonsils). There are several subsets of T cells, each with a distinctfunction.

T helper cells (T_(H) cells) assist other white blood cells inimmunologic processes, including maturation of B cells into plasma cellsand memory B cells, and activation of cytotoxic T cells and macrophages.These cells are also known as CD4+ T cells because they express the CD4glycoprotein on their surface. Helper T cells become activated when theyare presented with peptide antigens by MHC class II molecules, which areexpressed on the surface of antigen-presenting cells (APCs). Onceactivated, they divide rapidly and secrete small proteins calledcytokines that regulate or assist in the active immune response. Thesecells can differentiate into one of several subtypes, including T_(H)1,T_(H)2, T_(H)3, T_(H)17, T_(H)9, or T_(FH), which secrete differentcytokines to facilitate a different type of immune response.

Cytotoxic T cells (T_(C) cells, or CTLs) destroy virally infected cellsand tumor cells, and are also implicated in transplant rejection. Thesecells are also known as CD8⁺ T cells since they express the CD8glycoprotein at their surface. These cells recognize their targets bybinding to antigen associated with MHC class I molecules, which arepresent on the surface of all nucleated cells. Through IL-10, adenosineand other molecules secreted by regulatory T cells, the CD8+ cells canbe inactivated to an anergic state, which prevents autoimmune diseases.

Memory T cells are a subset of antigen-specific T cells that persistlong-term after an infection has resolved. They quickly expand to largenumbers of effector T cells upon re-exposure to their cognate antigen,thus providing the immune system with “memory” against past infections.Memory cells may be either CD4⁺ or CD8⁺. Memory T cells typicallyexpress the cell surface protein CD45RO.

Regulatory T cells (To cells), formerly known as suppressor T cells, arecrucial for the maintenance of immunological tolerance. Their major roleis to shut down T cell-mediated immunity toward the end of an immunereaction and to suppress auto-reactive T cells that escaped the processof negative selection in the thymus. Two major classes of CD4⁺ T_(reg)cells have been described—naturally occurring T_(reg) cells and adaptiveT_(reg) cells.

Natural killer T (NKT) cells (not to be confused with natural killer(NK) cells) bridge the adaptive immune system with the innate immunesystem. Unlike conventional T cells that recognize peptide antigenspresented by major histocompatibility complex (MHC) molecules, NKT cellsrecognize glycolipid antigen presented by a molecule called CD1d.

In some embodiments, the T cells comprise a mixture of CD4+ cells. Inother embodiments, the T cells are enriched for one or more subsetsbased on cell surface expression. For example, in some cases, the Tcomprise are cytotoxic CD8⁺ T lymphocytes. In some embodiments, the Tcells comprise γδ T cells, which possess a distinct T-cell receptor(TCR) having one γ chain and one δ chain instead of a and β chains.

Natural-killer (NK) cells are CD56⁺CD3⁻ large granular lymphocytes thatcan kill virally infected and transformed cells, and constitute acritical cellular subset of the innate immune system (Godfrey J, et al.Leuk Lymphoma 2012 53:1666-1676).

Unlike cytotoxic CD8⁺ T lymphocytes, NK cells launch cytotoxicityagainst tumor cells without the requirement for prior sensitization, andcan also eradicate MHC-I-negative cells (Nami-Mancinelli E, et al. IntImmunol 2011 23:427-431). NK cells are safer effector cells, as they mayavoid the potentially lethal complications of cytokine storms (Morgan RA, et al. Mol Ther 2010 18:843-851), tumor lysis syndrome (Porter D L,et al. N Engl J Med 2011 365:725-733), and on-target, off-tumor effects.Although NK cells have a well-known role as killers of cancer cells, andNK cell impairment has been extensively documented as crucial forprogression of MM (Godfrey J, et al. Leuk Lymphoma 2012 53:1666-1676;Fauriat C, et al. Leukemia 2006 20:732-733), the means by which onemight enhance NK cell-mediated anti-MM activity has been largelyunexplored prior to the disclosed CARs.

Therapeutic Methods

Immune effector cells expressing the disclosed CARs can elicit ananti-tumor immune response against TIM3-expressing cancer cells. Theanti-tumor immune response elicited by the disclosed CAR-modified immuneeffector cells may be an active or a passive immune response. Inaddition, the CAR-mediated immune response may be part of an adoptiveimmunotherapy approach in which CAR-modified immune effector cellsinduce an immune response specific to TIM3.

Adoptive transfer of immune effector cells expressing chimeric antigenreceptors is a promising anti-cancer therapeutic. Following thecollection of a patient's immune effector cells, the cells may begenetically engineered to express the disclosed TIM3-specific CARs, theninfused back into the patient.

The disclosed CAR-modified immune effector cells may be administeredeither alone, or as a pharmaceutical composition in combination withdiluents and/or with other components such as IL-2, IL-15, or othercytokines or cell populations. Briefly, pharmaceutical compositions maycomprise a target cell population as described herein, in combinationwith one or more pharmaceutically or physiologically acceptablecarriers, diluents or excipients. Such compositions may comprise bufferssuch as neutral buffered saline, phosphate buffered saline and the like;carbohydrates such as glucose, mannose, sucrose or dextrans, mannitol;proteins; polypeptides or amino acids such as glycine; antioxidants;chelating agents such as EDTA or glutathione; adjuvants (e.g., aluminumhydroxide); and preservatives. Compositions for use in the disclosedmethods are in some embodiments formulated for intravenousadministration. Pharmaceutical compositions may be administered in anymanner appropriate treat MM. The quantity and frequency ofadministration will be determined by such factors as the condition ofthe patient, and the severity of the patient's disease, althoughappropriate dosages may be determined by clinical trials.

When “an immunologically effective amount”, “an anti-tumor effectiveamount”, “an tumor-inhibiting effective amount”, or “therapeutic amount”is indicated, the precise amount of the compositions of the presentinvention to be administered can be determined by a physician withconsideration of individual differences in age, weight, tumor size,extent of infection or metastasis, and condition of the patient(subject). It can generally be stated that a pharmaceutical compositioncomprising the T cells described herein may be administered at a dosageof 10⁴ to 10⁹ cells/kg body weight, such as 10⁵ to 10⁶ cells/kg bodyweight, including all integer values within those ranges. T cellcompositions may also be administered multiple times at these dosages.The cells can be administered by using infusion techniques that arecommonly known in immunotherapy (see, e.g., Rosenberg et al., New Eng.J. of Med. 319:1676, 1988). The optimal dosage and treatment regime fora particular patient can readily be determined by one skilled in the artof medicine by monitoring the patient for signs of disease and adjustingthe treatment accordingly.

In certain embodiments, it may be desired to administer activated Tcells to a subject and then subsequently re-draw blood (or have anapheresis performed), activate T cells therefrom according to thedisclosed methods, and reinfuse the patient with these activated andexpanded T cells. This process can be carried out multiple times everyfew weeks. In certain embodiments, T cells can be activated from blooddraws of from 10 cc to 400 cc. In certain embodiments, T cells areactivated from blood draws of 20 cc, 30 cc, 40 cc, 50 cc, 60 cc, 70 cc,80 cc, 90 cc, or 100 cc. Using this multiple blood draw/multiplereinfusion protocol may serve to select out certain populations of Tcells.

The administration of the disclosed compositions may be carried out inany convenient manner, including by injection, transfusion, orimplantation. The compositions described herein may be administered to apatient subcutaneously, intradermally, intratumorally, intranodally,intramedullary, intramuscularly, by intravenous (i.v.) injection, orintraperitoneally. In some embodiments, the disclosed compositions areadministered to a patient by intradermal or subcutaneous injection. Insome embodiments, the disclosed compositions are administered by i.v.injection. The compositions may also be injected directly into a tumor,lymph node, or site of infection.

In certain embodiments, the disclosed CAR-modified immune effector cellsare administered to a patient in conjunction with (e.g., before,simultaneously or following) any number of relevant treatmentmodalities, including but not limited to thalidomide, dexamethasone,bortezomib, and lenalidomide. In further embodiments, the CAR-modifiedimmune effector cells may be used in combination with chemotherapy,radiation, immunosuppressive agents, such as cyclosporin, azathioprine,methotrexate, mycophenolate, and FK506, antibodies, or otherimmunoablative agents such as CAM PATH, anti-CD3 antibodies or otherantibody therapies, cytoxin, fludaribine, cyclosporin, FK506, rapamycin,mycophenolic acid, steroids, FR901228, cytokines, and irradiation. Insome embodiments, the CAR-modified immune effector cells areadministered to a patient in conjunction with (e.g., before,simultaneously or following) bone marrow transplantation, T cellablative therapy using either chemotherapy agents such as, fludarabine,external-beam radiation therapy (XRT), cyclophosphamide, or antibodiessuch as OKT3 or CAMPATH. In another embodiment, the cell compositions ofthe present invention are administered following B-cell ablative therapysuch as agents that react with CD20, e.g., Rituxan. For example, in someembodiments, subjects may undergo standard treatment with high dosechemotherapy followed by peripheral blood stem cell transplantation. Incertain embodiments, following the transplant, subjects receive aninfusion of the expanded immune cells of the present invention. In anadditional embodiment, expanded cells are administered before orfollowing surgery.

The cancer of the disclosed methods can be any TIM3-expressing cell in asubject undergoing unregulated growth, invasion, or metastasis. Cancersthat express TIM3 include hematological cancers, such as acute myeloidleukemia (AML), myelodysplasia, cervical cancer, gastric cancer,melanoma, and lung cancer.

In some aspects, the cancer can be any neoplasm or tumor for whichradiotherapy is currently used. Alternatively, the cancer can be aneoplasm or tumor that is not sufficiently sensitive to radiotherapyusing standard methods. Thus, the cancer can be a sarcoma, lymphoma,leukemia, carcinoma, blastoma, or germ cell tumor. A representative butnon-limiting list of cancers that the disclosed compositions can be usedto treat include lymphoma, B cell lymphoma, T cell lymphoma, mycosisfungoides, Hodgkin's Disease, myeloid leukemia, bladder cancer, braincancer, nervous system cancer, head and neck cancer, squamous cellcarcinoma of head and neck, kidney cancer, lung cancers such as smallcell lung cancer and non-small cell lung cancer,neuroblastoma/glioblastoma, ovarian cancer, pancreatic cancer, prostatecancer, skin cancer, liver cancer, melanoma, squamous cell carcinomas ofthe mouth, throat, larynx, and lung, endometrial cancer, cervicalcancer, cervical carcinoma, breast cancer, epithelial cancer, renalcancer, genitourinary cancer, pulmonary cancer, esophageal carcinoma,head and neck carcinoma, large bowel cancer, hematopoietic cancers;testicular cancer; colon and rectal cancers, prostatic cancer, andpancreatic cancer.

The disclosed CARs can be used in combination with any compound, moietyor group which has a cytotoxic or cytostatic effect. Drug moietiesinclude chemotherapeutic agents, which may function as microtubulininhibitors, mitosis inhibitors, topoisomerase inhibitors, or DNAintercalators, and particularly those which are used for cancer therapy.

The disclosed CARs can be used in combination with a checkpointinhibitor. The two known inhibitory checkpoint pathways involvesignaling through the cytotoxic T-lymphocyte antigen-4 (CTLA-4) andprogrammed-death 1 (PD-1) receptors. These proteins are members of theCD28-B7 family of cosignaling molecules that play important rolesthroughout all stages of T cell function. The PD-1 receptor (also knownas CD279) is expressed on the surface of activated T cells. Its ligands,PD-L1 (B7-H1; CD274) and PD-L2 (B7-DC; CD273), are expressed on thesurface of APCs such as dendritic cells or macrophages. PD-L1 is thepredominant ligand, while PD-L2 has a much more restricted expressionpattern. When the ligands bind to PD-1, an inhibitory signal istransmitted into the T cell, which reduces cytokine production andsuppresses T-cell proliferation. Checkpoint inhibitors include, but arenot limited to antibodies that block PD-1 (Nivolumab (BMS-936558 orMDX1106), CT-011, MK-3475), PD-L1 (MDX-1105 (BMS-936559), MPDL3280A,MSB0010718C), PD-L2 (rHIgM12B7), CTLA-4 (Ipilimumab (MDX-010),Tremelimumab (CP-675,206)), IDO, B7-H3 (MGA271), B7-H4, TIM3, LAG-3(BMS-986016).

Human monoclonal antibodies to programmed death 1 (PD-1) and methods fortreating cancer using anti-PD-1 antibodies alone or in combination withother immunotherapeutics are described in U.S. Pat. No. 8,008,449, whichis incorporated by reference for these antibodies. Anti-PD-L1 antibodiesand uses therefor are described in U.S. Pat. No. 8,552,154, which isincorporated by reference for these antibodies. Anticancer agentcomprising anti-PD-1 antibody or anti-PD-L1 antibody are described inU.S. Pat. No. 8,617,546, which is incorporated by reference for theseantibodies.

In some embodiments, the PDL1 inhibitor comprises an antibody thatspecifically binds PDL1, such as BMS-936559 (Bristol-Myers Squibb) orMPDL3280A (Roche). In some embodiments, the PD1 inhibitor comprises anantibody that specifically binds PD1, such as lambrolizumab (Merck),nivolumab (Bristol-Myers Squibb), or MED14736 (AstraZeneca). Humanmonoclonal antibodies to PD-1 and methods for treating cancer usinganti-PD-1 antibodies alone or in combination with otherimmunotherapeutics are described in U.S. Pat. No. 8,008,449, which isincorporated by reference for these antibodies. Anti-PD-L1 antibodiesand uses therefor are described in U.S. Pat. No. 8,552,154, which isincorporated by reference for these antibodies. Anticancer agentcomprising anti-PD-1 antibody or anti-PD-L1 antibody are described inU.S. Pat. No. 8,617,546, which is incorporated by reference for theseantibodies.

The disclosed CARs can be used in combination with other cancerimmunotherapies. There are two distinct types of immunotherapy: passiveimmunotherapy uses components of the immune system to direct targetedcytotoxic activity against cancer cells, without necessarily initiatingan immune response in the patient, while active immunotherapy activelytriggers an endogenous immune response. Passive strategies include theuse of the monoclonal antibodies (mAbs) produced by B cells in responseto a specific antigen. The development of hybridoma technology in the1970s and the identification of tumor-specific antigens permitted thepharmaceutical development of mAbs that could specifically target tumorcells for destruction by the immune system. Thus far, mAbs have been thebiggest success story for immunotherapy; the top three best-sellinganticancer drugs in 2012 were mAbs. Among them is rituximab (Rituxan,Genentech), which binds to the CD20 protein that is highly expressed onthe surface of B cell malignancies such as non-Hodgkin's lymphoma (NHL).Rituximab is approved by the FDA for the treatment of NHL and chroniclymphocytic leukemia (CLL) in combination with chemotherapy. Anotherimportant mAb is trastuzumab (Herceptin; Genentech), whichrevolutionized the treatment of HER2 (human epidermal growth factorreceptor 2)-positive breast cancer by targeting the expression of HER2.

Generating optimal “killer” CD8 T cell responses also requires T cellreceptor activation plus co-stimulation, which can be provided throughligation of tumor necrosis factor receptor family members, includingOX40 (CD134) and 4-1 BB (CD137). OX40 is of particular interest astreatment with an activating (agonist) anti-OX40 mAb augments T celldifferentiation and cytolytic function leading to enhanced anti-tumorimmunity against a variety of tumors.

In some embodiments, such an additional therapeutic agent may beselected from an antimetabolite, such as methotrexate, 6-mercaptopurine,6-thioguanine, cytarabine, fludarabine, 5-fluorouracil, decarbazine,hydroxyurea, asparaginase, gemcitabine or cladribine.

In some embodiments, such an additional therapeutic agent may beselected from an alkylating agent, such as mechlorethamine, thioepa,chlorambucil, melphalan, carmustine (BSNU), lomustine (CCNU),cyclophosphamide, busulfan, dibromomannitol, streptozotocin, dacarbazine(DTIC), procarbazine, mitomycin C, cisplatin and other platinumderivatives, such as carboplatin.

In some embodiments, such an additional therapeutic agent may beselected from an anti-mitotic agent, such as taxanes, for instancedocetaxel, and paclitaxel, and vinca alkaloids, for instance vindesine,vincristine, vinblastine, and vinorelbine.

In some embodiments, such an additional therapeutic agent may beselected from a topoisomerase inhibitor, such as topotecan oririnotecan, or a cytostatic drug, such as etoposide and teniposide.

In some embodiments, such an additional therapeutic agent may beselected from a growth factor inhibitor, such as an inhibitor of ErbBl(EGFR) (such as an EGFR antibody, e.g. zalutumumab, cetuximab,panitumumab or nimotuzumab or other EGFR inhibitors, such as gefitinibor erlotinib), another inhibitor of ErbB2 (HER2/neu) (such as a HER2antibody, e.g. trastuzumab, trastuzumab-DM 1 or pertuzumab) or aninhibitor of both EGFR and HER2, such as lapatinib).

In some embodiments, such an additional therapeutic agent may beselected from a tyrosine kinase inhibitor, such as imatinib (Glivec,Gleevec STI571) or lapatinib.

Therefore, in some embodiments, a disclosed antibody is used incombination with ofatumumab, zanolimumab, daratumumab, ranibizumab,nimotuzumab, panitumumab, hu806, daclizumab (Zenapax), basiliximab(Simulect), infliximab (Remicade), adalimumab (Humira), natalizumab(Tysabri), omalizumab (Xolair), efalizumab (Raptiva), and/or rituximab.

In some embodiments, a therapeutic agent for use in combination with aCARs for treating the disorders as described above may be an anti-cancercytokine, chemokine, or combination thereof. Examples of suitablecytokines and growth factors include IFNy, IL-2, IL-4, IL-6, IL-7,IL-10, IL-12, IL-13, IL-15, IL-18, IL-23, IL-24, IL-27, IL-28a, IL-28b,IL-29, KGF, IFNa (e.g., INFa2b), IFN, GM-CSF, CD40L, Flt3 ligand, stemcell factor, ancestim, and TNFa. Suitable chemokines may includeGlu-Leu-Arg (ELR)-negative chemokines such as IP-10, MCP-3, MIG, andSDF-1a from the human CXC and C—C chemokine families. Suitable cytokinesinclude cytokine derivatives, cytokine variants, cytokine fragments, andcytokine fusion proteins.

In some embodiments, a therapeutic agent for use in combination with aCARs for treating the disorders as described above may be a cell cyclecontrol/apoptosis regulator (or “regulating agent”). A cell cyclecontrollapoptosis regulator may include molecules that target andmodulate cell cycle controllapoptosis regulators such as (i) cdc-25(such as NSC 663284), (ii) cyclin-dependent kinases that overstimulatethe cell cycle (such as flavopiridol (L868275, HMR1275),7-hydroxystaurosporine (UCN-01, KW-2401), and roscovitine(R-roscovitine, CYC202)), and (iii) telomerase modulators (such asBIBR1532, SOT-095, GRN163 and compositions described in for instanceU.S. Pat. Nos. 6,440,735 and 6,713,055). Non-limiting examples ofmolecules that interfere with apoptotic pathways include TNF-relatedapoptosis-inducing ligand (TRAIL)/apoptosis-2 ligand (Apo-2L),antibodies that activate TRAIL receptors, IFNs, and anti-sense Bcl-2.

In some embodiments, a therapeutic agent for use in combination with aCARs for treating the disorders as described above may be a hormonalregulating agent, such as agents useful for anti-androgen andanti-estrogen therapy. Examples of such hormonal regulating agents aretamoxifen, idoxifene, fulvestrant, droloxifene, toremifene, raloxifene,diethylstilbestrol, ethinyl estradiol/estinyl, an antiandrogene (such asflutaminde/eulexin), a progestin (such as such as hydroxyprogesteronecaproate, medroxy-progesterone/provera, megestrol acepate/megace), anadrenocorticosteroid (such as hydrocortisone, prednisone), luteinizinghormone-releasing hormone (and analogs thereof and other LHRH agonistssuch as buserelin and goserelin), an aromatase inhibitor (such asanastrazole/arimidex, aminoglutethimide/cytraden, exemestane) or ahormone inhibitor (such as octreotide/sandostatin).

In some embodiments, a therapeutic agent for use in combination with anCARs for treating the disorders as described above may be an anti-cancernucleic acid or an anti-cancer inhibitory RNA molecule.

Combined administration, as described above, may be simultaneous,separate, or sequential. For simultaneous administration the agents maybe administered as one composition or as separate compositions, asappropriate.

In some embodiments, the disclosed CARs is administered in combinationwith radiotherapy. Radiotherapy may comprise radiation or associatedadministration of radiopharmaceuticals to a patient is provided. Thesource of radiation may be either external or internal to the patientbeing treated (radiation treatment may, for example, be in the form ofexternal beam radiation therapy (EBRT) or brachytherapy (BT)).Radioactive elements that may be used in practicing such methodsinclude, e.g., radium, cesium-137, iridium-192, americium-241, gold-198,cobalt-57, copper-67, technetium-99, iodide-123, iodide-131, andindium-111.

In some embodiments, the disclosed CARs is administered in combinationwith surgery.

CAR-T cells may be designed in several ways that enhance tumorcytotoxicity and specificity, evade tumor immunosuppression, avoid hostrejection, and prolong their therapeutic half-life. TRUCK (T-cellsRedirected for Universal Cytokine Killing) T cells for example, possessa CAR but are also engineered to release cytokines such as IL-12 thatpromote tumor killing. Because these cells are designed to release amolecular payload upon activation of the CAR once localized to the tumorenvironment, these CAR-T cells are sometimes also referred to as‘armored CARs’. Several cytokines as cancer therapies are beinginvestigated both pre-clinically and clinically, and may also proveuseful when similarly incorporated into a TRUCK form of CAR-T therapy.Among these include IL-2, IL-3. IL-4, IL-5, IL-6, IL-7, IL-10, IL-12,IL-13, IL-15, IL-18, M-CSF, GM-CSF, IFN-α, IFN-γ, TNF-α, TRAIL, FLT3ligand, Lymphotactin, and TGF-β (Dranoff 2004). “Self-driving” or“homing” CAR-T cells are engineered to express a chemokine receptor inaddition to their CAR. As certain chemokines can be upregulated intumors, incorporation of a chemokine receptor aids in tumor traffickingto and infiltration by the adoptive T-cell, thereby enhancing bothspecificity and functionality of the CAR-T (Moon 2011). Universal CAR-Tcells also possess a CAR, but are engineered such that they do notexpress endogenous TCR (T-cell receptor) or MHC (majorhistocompatibility complex) proteins. Removal of these two proteins fromthe signaling repertoire of the adoptive T-cell therapy preventsgraft-versus-host-disease and rejection, respectively. Armored CAR-Tcells are additionally so named for their ability to evade tumorimmunosuppression and tumor-induced CAR-T hypofunction. These particularCAR-Ts possess a CAR, and may be engineered to not express checkpointinhibitors. Alternatively, these CAR-Ts can be co-administered with amonoclonal antibody (mAb) that blocks checkpoint signaling.Administration of an anti-PDL1 antibody significantly restored thekilling ability of CAR TILs (tumor infiltrating lymphocytes). WhilePD1-PDL1 and CTLA-4-CD80/CD86 signaling pathways have been investigated,it is possible to target other immune checkpoint signaling molecules inthe design of an armored CAR-T including LAG-3, Tim-3, IDO-1, 2B4, andKIR. Other intracellular inhibitors of TILs include phosphatases (SHP1),ubiquitin-ligases (i.e., cbl-b), and kinases (i.e., diacyiglycerolkinase). Armored CAR-Ts may also be engineered to express proteins orreceptors that protect them against or make them resistant to theeffects of tumor-secreted cytokines. For example, CTLs (cytotoxic Tlymphocytes) transduced with the double negative form of the TGF-βreceptor are resistant to the immunosuppression by lymphoma secretedTGF-β. These transduced cells showed notably increased antitumoractivity in vivo when compared to their control counterparts.

Tandem and dual CAR-T cells are unique in that they possess two distinctantigen binding domains. A tandem CAR contains two sequential antigenbinding domains facing the extracellular environment connected to theintracellular costimulatory and stimulatory domains. A dual CAR isengineered such that one extracellular antigen binding domain isconnected to the intracellular costimulatory domain and a second,distinct extracellular antigen binding domain is connected to theintracellular stimulatory domain. Because the stimulatory andcostimulatory domains are split between two separate antigen bindingdomains, dual CARs are also referred to as “split CARs”. In both tandemand dual CAR designs, binding of both antigen binding domains isnecessary to allow signaling of the CAR circuit in the T-cell. Becausethese two CAR designs have binding affinities for different, distinctantigens, they are also referred to as “bi-specific” CARs.

One primary concern with CAR-T cells as a form of “living therapeutic”is their manipulability in vivo and their potential immune-stimulatingside effects. To better control CAR-T therapy and prevent againstunwanted side effects, a variety of features have been engineeredincluding off-switches, safety mechanisms, and conditional controlmechanisms. Both self-destruct and marked/tagged CAR-T cells forexample, are engineered to have an “off-switch” that promotes clearanceof the CAR-expressing T-cell. A self-destruct CAR-T contains a CAR, butis also engineered to express a pro-apoptotic suicide gene or“elimination gene” inducible upon administration of an exogenousmolecule. A variety of suicide genes may be employed for this purpose,including HSV-TK (herpes simplex virus thymidine kinase), Fas, iCasp9(inducible caspase 9), CD20, MYC tag, and truncated EGFR (endothelialgrowth factor receptor). HSK for example, will convert the prodrugganciclovir (GCV) into GCV-triphosphate that incorporates itself intoreplicating DNA, ultimately leading to cell death. iCasp9 is a chimericprotein containing components of FK506-binding protein that binds thesmall molecule AP1903, leading to caspase 9 dimerization and apoptosis.A marked/tagged CAR-T cell however, is one that possesses a CAR but alsois engineered to express a selection marker. Administration of a mAbagainst this selection marker will promote clearance of the CAR-T cell.Truncated EGFR is one such targetable antigen by the anti-EGFR mAb, andadministration of cetuximab works to promotes elimination of the CAR-Tcell. CARs created to have these features are also referred to as sCARsfor ‘switchable CARs’, and RCARs for ‘regulatable CARs’. A “safety CAR”,also known as an “inhibitory CAR” (iCAR), is engineered to express twoantigen binding domains. One of these extracellular domains is directedagainst a tumor related antigen and bound to an intracellularcostimulatory and stimulatory domain. The second extracellular antigenbinding domain however is specific for normal tissue and bound to anintracellular checkpoint domain such as CTLA4, PD1, or CD45.Incorporation of multiple intracellular inhibitory domains to the iCARis also possible. Some inhibitory molecules that may provide theseinhibitory domains include B7-H1, B7-1, CD160, PIH, 2B4, CEACAM(CEACAM-1. CEACAM-3, and/or CEACAM-5), LAG-3, TIGIT, BTLA, LAIR1, andTGFβ-R. In the presence of normal tissue, stimulation of this secondantigen binding domain will work to inhibit the CAR. It should be notedthat due to this dual antigen specificity, iCARs are also a form ofbi-specific CAR-T cells. The safety CAR-T engineering enhancesspecificity of the CAR-T cell for tumor tissue, and is advantageous insituations where certain normal tissues may express very low levels of atumor associated antigen that would lead to off target effects with astandard CAR (Morgan 2010). A conditional CAR-T cell expresses anextracellular antigen binding domain connected to an intracellularcostimulatory domain and a separate, intracellular costimulator. Thecostimulatory and stimulatory domain sequences are engineered in such away that upon administration of an exogenous molecule the resultantproteins will come together intracellularly to complete the CAR circuit.In this way, CAR-T activation can be modulated, and possibly even‘fine-tuned’ or personalized to a specific patient. Similar to a dualCAR design, the stimulatory and costimulatory domains are physicallyseparated when inactive in the conditional CAR; for this reason thesetoo are also referred to as a “split CAR”.

In some embodiments, two or more of these engineered features may becombined to create an enhanced, multifunctional CAR-T. For example, itis possible to create a CAR-T cell with either dual- or conditional-CARdesign that also releases cytokines like a TRUCK. In some embodiments, adual-conditional CAR-T cell could be made such that it expresses twoCARs with two separate antigen binding domains against two distinctcancer antigens, each bound to their respective costimulatory domains.The costimulatory domain would only become functional with thestimulatory domain after the activating molecule is administered. Forthis CAR-T cell to be effective the cancer must express both cancerantigens and the activating molecule must be administered to thepatient; this design thereby incorporating features of both dual andconditional CAR-T cells.

Typically, CAR-T cells are created using α-β T cells, however γ-δ Tcells may also be used. In some embodiments, the described CARconstructs, domains, and engineered features used to generate CAR-Tcells could similarly be employed in the generation of other types ofCAR-expressing immune cells including NK (natural killer) cells, Bcells, mast cells, myeloid-derived phagocytes, and NKT cells.Alternatively, a CAR-expressing cell may be created to have propertiesof both T-cell and NK cells. In an additional embodiment, the transducedwith CARs may be autologous or allogeneic.

Several different methods for CAR expression may be used includingretroviral transduction (including γ-retroviral), lentiviraltransduction, transposon/transposases (Sleeping Beauty and PiggyBacsystems), and messenger RNA transfer-mediated gene expression. Geneediting (gene insertion or gene deletion/disruption) has become ofincreasing importance with respect to the possibility for engineeringCAR-T cells as well. CRISPR-Cas9, ZFN (zinc finger nuclease), and TALEN(transcription activator like effector nuclease) systems are threepotential methods through which CAR-T cells may be generated.

Definitions

The term “amino acid sequence” refers to a list of abbreviations,letters, characters or words representing amino acid residues. The aminoacid abbreviations used herein are conventional one letter codes for theamino acids and are expressed as follows: A, alanine; B, asparagine oraspartic acid; C, cysteine; D aspartic acid; E, glutamate, glutamicacid; F, phenylalanine; G, glycine; H histidine; I isoleucine; K,lysine; L, leucine; M, methionine; N, asparagine; P, proline; Q,glutamine; R, arginine; S, serine; T, threonine; V, valine; W,tryptophan; Y, tyrosine; Z, glutamine or glutamic acid.

The term “antibody” refers to an immunoglobulin, derivatives thereofwhich maintain specific binding ability, and proteins having a bindingdomain which is homologous or largely homologous to an immunoglobulinbinding domain. These proteins may be derived from natural sources, orpartly or wholly synthetically produced. An antibody may be monoclonalor polyclonal. The antibody may be a member of any immunoglobulin classfrom any species, including any of the human classes: IgG, IgM, IgA,IgD, and IgE. In exemplary embodiments, antibodies used with the methodsand compositions described herein are derivatives of the IgG class. Inaddition to intact immunoglobulin molecules, also included in the term“antibodies” are fragments or polymers of those immunoglobulinmolecules, and human or humanized versions of immunoglobulin moleculesthat selectively bind the target antigen.

The term “aptamer” refers to oligonucleic acid or peptide molecules thatbind to a specific target molecule. These molecules are generallyselected from a random sequence pool. The selected aptamers are capableof adapting unique tertiary structures and recognizing target moleculeswith high affinity and specificity. A “nucleic acid aptamer” is a DNA orRNA oligonucleic acid that binds to a target molecule via itsconformation, and thereby inhibits or suppresses functions of suchmolecule. A nucleic acid aptamer may be constituted by DNA, RNA, or acombination thereof. A “peptide aptamer” is a combinatorial proteinmolecule with a variable peptide sequence inserted within a constantscaffold protein. Identification of peptide aptamers is typicallyperformed under stringent yeast dihybrid conditions, which enhances theprobability for the selected peptide aptamers to be stably expressed andcorrectly folded in an intracellular context.

The term “carrier” means a compound, composition, substance, orstructure that, when in combination with a compound or composition, aidsor facilitates preparation, storage, administration, delivery,effectiveness, selectivity, or any other feature of the compound orcomposition for its intended use or purpose. For example, a carrier canbe selected to minimize any degradation of the active ingredient and tominimize any adverse side effects in the subject.

The term “chimeric molecule” refers to a single molecule created byjoining two or more molecules that exist separately in their nativestate. The single, chimeric molecule has the desired functionality ofall of its constituent molecules. One type of chimeric molecules is afusion protein.

The term “fusion protein” refers to a polypeptide formed by the joiningof two or more polypeptides through a peptide bond formed between theamino terminus of one polypeptide and the carboxyl terminus of anotherpolypeptide. The fusion protein can be formed by the chemical couplingof the constituent polypeptides or it can be expressed as a singlepolypeptide from nucleic acid sequence encoding the single contiguousfusion protein. A single chain fusion protein is a fusion protein havinga single contiguous polypeptide backbone. Fusion proteins can beprepared using conventional techniques in molecular biology to join thetwo genes in frame into a single nucleic acid, and then expressing thenucleic acid in an appropriate host cell under conditions in which thefusion protein is produced.

The term “identity” refers to sequence identity between two nucleic acidmolecules or polypeptides. Identity can be determined by comparing aposition in each sequence which may be aligned for purposes ofcomparison. When a position in the compared sequence is occupied by thesame base, then the molecules are identical at that position. A degreeof similarity or identity between nucleic acid or amino acid sequencesis a function of the number of identical or matching nucleotides atpositions shared by the nucleic acid sequences. Various alignmentalgorithms and/or programs may be used to calculate the identity betweentwo sequences, including FASTA, or BLAST which are available as a partof the GCG sequence analysis package (University of Wisconsin, Madison,Wis.), and can be used with, e.g., default setting. For example,polypeptides having at least 70%, 85%, 90%, 95%, 98% or 99% identity tospecific polypeptides described herein and preferably exhibitingsubstantially the same functions, as well as polynucleotide encodingsuch polypeptides, are contemplated. Unless otherwise indicated asimilarity score will be based on use of BLOSUM62. When BLASTP is used,the percent similarity is based on the BLASTP positives score and thepercent sequence identity is based on the BLASTP identities score.BLASTP “Identities” shows the number and fraction of total residues inthe high scoring sequence pairs which are identical; and BLASTP“Positives” shows the number and fraction of residues for which thealignment scores have positive values and which are similar to eachother. Amino acid sequences having these degrees of identity orsimilarity or any intermediate degree of identity of similarity to theamino acid sequences disclosed herein are contemplated and encompassedby this disclosure. The polynucleotide sequences of similar polypeptidesare deduced using the genetic code and may be obtained by conventionalmeans, in particular by reverse translating its amino acid sequenceusing the genetic code.

The term “nucleic acid” refers to a natural or synthetic moleculecomprising a single nucleotide or two or more nucleotides linked by aphosphate group at the 3′ position of one nucleotide to the 5′ end ofanother nucleotide. The nucleic acid is not limited by length, and thusthe nucleic acid can include deoxyribonucleic acid (DNA) or ribonucleicacid (RNA).

The term “operably linked to” refers to the functional relationship of anucleic acid with another nucleic acid sequence. Promoters, enhancers,transcriptional and translational stop sites, and other signal sequencesare examples of nucleic acid sequences operably linked to othersequences. For example, operable linkage of DNA to a transcriptionalcontrol element refers to the physical and functional relationshipbetween the DNA and promoter such that the transcription of such DNA isinitiated from the promoter by an RNA polymerase that specificallyrecognizes, binds to and transcribes the DNA.

The terms “peptide,” “protein,” and “polypeptide” are usedinterchangeably to refer to a natural or synthetic molecule comprisingtwo or more amino acids linked by the carboxyl group of one amino acidto the alpha amino group of another.

The term “pharmaceutically acceptable” refers to those compounds,materials, compositions, and/or dosage forms which are, within the scopeof sound medical judgment, suitable for use in contact with the tissuesof human beings and animals without excessive toxicity, irritation,allergic response, or other problems or complications commensurate witha reasonable benefit/risk ratio.

The term “protein domain” refers to a portion of a protein, portions ofa protein, or an entire protein showing structural integrity; thisdetermination may be based on amino acid composition of a portion of aprotein, portions of a protein, or the entire protein.

A “spacer” as used herein refers to a peptide that joins the proteinscomprising a fusion protein. Generally a spacer has no specificbiological activity other than to join the proteins or to preserve someminimum distance or other spatial relationship between them. However,the constituent amino acids of a spacer may be selected to influencesome property of the molecule such as the folding, net charge, orhydrophobicity of the molecule.

The term “specifically binds”, as used herein, when referring to apolypeptide (including antibodies) or receptor, refers to a bindingreaction which is determinative of the presence of the protein orpolypeptide or receptor in a heterogeneous population of proteins andother biologics. Thus, under designated conditions (e.g. immunoassayconditions in the case of an antibody), a specified ligand or antibody“specifically binds” to its particular “target” (e.g. an antibodyspecifically binds to an endothelial antigen) when it does not bind in asignificant amount to other proteins present in the sample or to otherproteins to which the ligand or antibody may come in contact in anorganism. Generally, a first molecule that “specifically binds” a secondmolecule has an affinity constant (Ka) greater than about 10^(s) M⁻¹(e.g., 10⁸ M⁻¹, 10⁷ M⁻¹, 10⁸ M⁻¹, 10⁹ M⁻¹, 10¹⁰ M⁻¹, 10¹¹ M⁻¹, and 10¹²M⁻¹ or more) with that second molecule.

The term “specifically deliver” as used herein refers to thepreferential association of a molecule with a cell or tissue bearing aparticular target molecule or marker and not to cells or tissues lackingthat target molecule. It is, of course, recognized that a certain degreeof non-specific interaction may occur between a molecule and anon-target cell or tissue. Nevertheless, specific delivery, may bedistinguished as mediated through specific recognition of the targetmolecule. Typically specific delivery results in a much strongerassociation between the delivered molecule and cells bearing the targetmolecule than between the delivered molecule and cells lacking thetarget molecule.

The term “subject” refers to any individual who is the target ofadministration or treatment. The subject can be a vertebrate, forexample, a mammal. Thus, the subject can be a human or veterinarypatient. The term “patient” refers to a subject under the treatment of aclinician, e.g., physician.

The term “therapeutically effective” refers to the amount of thecomposition used is of sufficient quantity to ameliorate one or morecauses or symptoms of a disease or disorder. Such amelioration onlyrequires a reduction or alteration, not necessarily elimination.

The terms “transformation” and “transfection” mean the introduction of anucleic acid, e.g., an expression vector, into a recipient cellincluding introduction of a nucleic acid to the chromosomal DNA of saidcell.

The term “treatment” refers to the medical management of a patient withthe intent to cure, ameliorate, stabilize, or prevent a disease,pathological condition, or disorder. This term includes activetreatment, that is, treatment directed specifically toward theimprovement of a disease, pathological condition, or disorder, and alsoincludes causal treatment, that is, treatment directed toward removal ofthe cause of the associated disease, pathological condition, ordisorder. In addition, this term includes palliative treatment, that is,treatment designed for the relief of symptoms rather than the curing ofthe disease, pathological condition, or disorder; preventativetreatment, that is, treatment directed to minimizing or partially orcompletely inhibiting the development of the associated disease,pathological condition, or disorder; and supportive treatment, that is,treatment employed to supplement another specific therapy directedtoward the improvement of the associated disease, pathologicalcondition, or disorder.

The term “variant” refers to an amino acid or peptide sequence havingconservative amino acid substitutions, non-conservative amino acidsubsitutions (i.e. a degenerate variant), substitutions within thewobble position of each codon (i.e. DNA and RNA) encoding an amino acid,amino acids added to the C-terminus of a peptide, or a peptide having60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99% sequence identity to areference sequence.

The term “vector” refers to a nucleic acid sequence capable oftransporting into a cell another nucleic acid to which the vectorsequence has been linked. The term “expression vector” includes anyvector, (e.g., a plasmid, cosmid or phage chromosome) containing a geneconstruct in a form suitable for expression by a cell (e.g., linked to atranscriptional control element).

A number of embodiments of the invention have been described.Nevertheless, it will be understood that various modifications may bemade without departing from the spirit and scope of the invention.Accordingly, other embodiments are within the scope of the followingclaims.

EXAMPLES Example 1

Mice were immunized, sacrificed, and spleens isolated. Splenocytes wereprepared as single cell suspensions and used to isolate RNA. The RNA wassubmitted for Genewiz IgH and IgL sequencing. Bioinformatics wasperformed to determine the most frequent rearrangements, whichpresumably would encode for anti-TIM3 reactivity. The sequences werethen used to develop scFv and design CARs with different pairs of IgHscFv and IgL scFv. These scFv were cloned into a retroviral constructand used to make virus and transduce T cells for validation

Example 2

Retrovirus was used to transduce T cells and used for a cytotoxicityassay (Real Time Cell Anlaysis) by incubating adherent targets and CAR Tcells. A similar assay was used to detect secretion of Interferon-gamma.But after 4 hours of stimulation the cells were fixed and analyzed forintracellular IFNgamma. Cytokines were also analyzed by secretionassays. Targets were mixed with CAR T cells and after an overnightincubated the supernatant was collected and assayed by Luminx for thecytokines noted tin the figures. For the in vivo study immune-deficientNSG mice were injected with primary AML. After engraftment of the AMLthe mice were treated with anti-TIM3 CAR T cells and blood was monitoredfor CAR T cell expansion and AML killing.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of skill in the artto which the disclosed invention belongs. Publications cited herein andthe materials for which they are cited are specifically incorporated byreference.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed by the following claims.

What is claimed is:
 1. A chimeric antigen receptor (CAR) polypeptide,comprising a TIM3 antigen binding domain, a transmembrane domain, asignaling domain, and a co-stimulatory signaling region, wherein theTIM3 antigen binding domain is an anti-TIM3 single-chain variablefragment (scFv) of an antibody having a heavy (V_(H)) and light (V_(L))chain that specifically binds TIM3, wherein the anti-TIM3 scFv V_(H)domain comprises the amino acid sequence SEQ ID NO:1 or 2, and whereinthe anti-TIM3 scFv V_(L) domain comprises the amino acid sequence SEQ IDNO:3, 4, 5, or
 6. 2. The polypeptide of claim 1, wherein the anti-TIM3scFv V_(H) domain comprises the amino acid sequence SEQ ID NO:1.
 3. Thepolypeptide of claim 1, wherein the costimulatory signaling regioncomprises the cytoplasmic domain of a costimulatory molecule selectedfrom the group consisting of CD27, CD28, 4-1BB, OX40, CD30, CD40, PD-1,ICOS, lymphocyte function-associated antigen-1 (LFA-1), CD2, CD7, LIGHT,NKG2C, B7-H3, a ligand that specifically binds with CD83, and anycombination thereof.
 4. The polypeptide of claim 1, wherein the CARpolypeptide is defined by the formula:SP-TIM3-HG-TM-CSR-SD; orSP-TIM3-HG-TM-SD-CSR wherein “SP” represents a signal peptide, wherein“TIM3” represents a TIM3-binding region, wherein “HG” represents andoptional hinge domain, wherein “TM” represents a transmembrane domain,wherein “CSR” represents a co-stimulatory signaling region, wherein “SD”represents a signaling domain, and wherein “-” represents a bivalentlinker.
 5. The polypeptide of claim 1, wherein the signaling domaincomprises a CD3 zeta (CD3ζ) signaling domain.
 6. A method of providingan anti-cancer immunity in a subject with a TIM3-expressing acutemyeloid leukemia (AML), cervical cancer or melanoma, the methodcomprising administering to the subject an effective amount of an immuneeffector cell genetically modified to express the CAR polypeptide ofclaim 1, thereby providing an anti-tumor immunity in the mammal.
 7. Themethod of claim 6, wherein the immune effector cell is selected from thegroup consisting of a T cell, a Natural Killer (NK) cell, a cytotoxic Tlymphocyte (CTL), and a regulatory T cell.
 8. The method of claim 6,further comprising administering to the subject a checkpoint inhibitor.9. The method of claim 8, wherein the checkpoint inhibitor comprises ananti-PD-1 antibody, anti-PD-L1 antibody, anti-CTLA-4 antibody, or acombination thereof.
 10. The method of claim 7, wherein the cancercomprises an acute myeloid leukemia (AML).
 11. The polypeptide of claim1, wherein the anti-TIM3 scFv V_(H) domain comprises the amino acidsequence SEQ ID NO:2.
 12. The polypeptide of claim 1, wherein theanti-TIM3 scFv comprises the amino acid sequence selected from the groupconsisting of SEQ ID NOs:15-22.